Asta Literature Retrieval: Pathophysiology and clinical mechanisms of ADan amyloidosis. Core disease mechanisms, molecular and cellular pathways...

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• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

• Authors: Kyung-Yil Lee
• Year: 2022
• Venue: Cell & Bioscience
• URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
• DOI: 10.1186/s13578-022-00920-5
• PMID: 36384812
• PMCID: 9668226
• Citations: 9
• Influential citations: 1
• Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
• Evidence snippets:
• Snippet 1 (score: 0.480) > They are usually fibrillar when visualized by electronic microscopy and can be detected by the Congo red stain method. The pathophysiology of amyloidosis remains unknown, but the associated diseases include those with genetic traits, such as ATTRv and AFib, and those with underlying diseases that are accompanied by abnormal immune reactions, such as AL and AA amyloidosis [91]. Furthermore, the clinical manifestations and pathologic findings, such as the components of the deposited amyloidogenic proteins and peptides, are different in each disease, whereas the structure and properties of the protein aggregates, such as their insolubility, protease resistance, birefringent staining with Congo red, and high beta-sheet content, are similar across diseases, as observed in the prion diseases. These findings suggest that a common immunopathogenesis is involved in prion diseases and non-prion amyloid diseases [92]. > Certain chronic progressive CNS diseases, including AD, PD, and HD, are associated with genetic traits, similar to familial CJG and GSS in prion diseases. The pathological hallmarks of these diseases include intracellular inclusion bodies, extracellular amyloid deposits with various components, and neuronal loss. Well-studied amyloid proteins are amyloid beta (Aβ) and phosphorylated tau in AD and α-synuclein in PD. Inclusion bodies and extracellular amyloid proteins, such as Lewy bodies in PD and neurofibrillary tangles (tau protein) in AD, are considered to play important etiopathogenetic roles in neurodegenerative diseases. However, some affected patients have no intracellular inclusion lesions, and the degree of inclusion-body involvement in the pathology findings is not related to the clinical severity of the diseases. Furthermore, multiple risk factors are related to the diseases [93]. There are genetic forms of these diseases, and experimental studies of gene-null mice for the tau protein or α-synuclein show that those genes do not play a significant role in disease phenotype, pathologic lesions, or disease progression [94,95].

[2] Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

• Authors: Hidehiko Ikura, J. Endo, Hiroki Kitakata, Hidenori Moriyama, M. Sano et al.
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/1450c3006397005e391453bb1d59585e7ecef7d9
• DOI: 10.3390/ijms23116336
• PMID: 35683015
• PMCID: 9181426
• Citations: 23
• Influential citations: 1
• Summary: The pathogenesis and treatment strategies for AL amyloidosis with respect to its molecular mechanisms are outlined and the mechanism of cellular and tissue damage, the mass effect due to amyloids deposition, as well as the toxicity of pre-fibrillar LC, is gradually being elucidated.
• Evidence snippets:
• Snippet 1 (score: 0.461) > In amyloid light-chain (AL) amyloidosis, small B-cell clones (mostly plasma cell clones) present in the bone marrow proliferate and secrete unstable monoclonal free light chains (FLCs), which form amyloid fibrils that deposit in the interstitial tissue, resulting in organ injury and dysfunction. AL amyloidosis progresses much faster than other types of amyloidosis, with a slight delay in diagnosis leading to a marked exacerbation of cardiomyopathy. In some cases, the resulting heart failure is so severe that chemotherapy cannot be administered, and death sometimes occurs within a few months. To date, many clinical studies have focused on therapeutics, especially chemotherapy, to treat this disease. Because it is necessary to promptly lower FLC, the causative protein of amyloid, to achieve a hematological response, various anticancer agents targeting neoplastic plasma cells are used for the treatment of this disease. In addition, many basic studies using human specimens to elucidate the pathophysiology of AL have been conducted. Gene mutations associated with AL, the characteristics of amyloidogenic LC, and the structural specificity of amyloid fibrils have been clarified. Regarding the mechanism of cellular and tissue damage, the mass effect due to amyloid deposition, as well as the toxicity of pre-fibrillar LC, is gradually being elucidated. This review outlines the pathogenesis and treatment strategies for AL amyloidosis with respect to its molecular mechanisms.

[3] New treatment strategies for Alzheimer's disease: is there a hope?

• Authors: I. Aprahamian, F. Stella, O. Forlenza
• Year: 2013
• Venue: The Indian Journal of Medical Research
• URL: https://www.semanticscholar.org/paper/ea073be2ee0f8291a441455f49ba13689e1440a9
• PMID: 24434253
• PMCID: 3868059
• Citations: 71
• Influential citations: 8
• Summary: The available evidence on the new therapeutic approaches that target amyloid and Tau pathology in AD are summarized, focusing on pharmaceutical compounds undergoing phase 2 and phase 3 randomized controlled trials.
• Evidence snippets:
• Snippet 1 (score: 0.450) > The recognition of core and secondary pathophysiological mechanisms in AD has led to the identification of molecular targets for the development of specific drugs. In fact, more than 200 pharmaceutical compounds are currently undergoing phase 2 and 3 trials 11 . These compounds can be grossly divided into anti-amyloid agents and drugs that target other pathological pathways. Anti-amyloid compounds can be subdivided into drugs designed to block or inhibit the overproduction or aggregation of Aβ, or to favour its clearance from the brain (Table I; Fig. 2) 20 , whereas the latter group can be subdivided according to predominant mechanism of action of the drug, i.e., neurotransmitter and cell-signalling agents, glial cell modulators, neuroprotective agents, and Tau-based therapies (Table II). Studies involving stem-cell and gene therapy are also under way, but at more incipient stages of experimental validation. > In AD, pathophysiological mechanisms change soluble Aβ peptides into fibrillary oligomers and insoluble fibrils, which accumulate extracellularly in the neural tissue and also in the intima of brain and systemic vessels 34 . Extracellular Aβ oligomers and fibrillary forms cause synaptic dysfunction, affect axons and dendritic spines, and eventually lead to neuronal loss in AD 35 . Toxic Aβ species also trigger secondary pathological mechanisms (e.g., oxidative stress and inflammation), which hasten neuronal dysfunction and death 36 . Therefore, pharmacological compounds that favour the clearance of Aβ from the brain, or prevent its aggregation, may represent a strategy to delay the progression of the pathological process in AD. Intracerebral amyloidosis may start in the brain of individuals with AD many years before the onset of clinical symptoms 37,38 . Evidence of this pathological process can be depicted at prodromal or even at preclinical stages of the disease by the analysis of cerebrospinal fluid (CSF) and molecular neuroimaging biomarkers [37][38][39] .

[4] Transthyretin mutagenesis: impact on amyloidogenesis and disease

• Authors: Zaida L. Almeida, D. Vaz, Rui M. M. Brito
• Year: 2024
• Venue: Critical Reviews in Clinical Laboratory Sciences
• URL: https://www.semanticscholar.org/paper/543c86839cb0c86a5ba2ea68fa8cc897ab376b55
• DOI: 10.1080/10408363.2024.2350379
• PMID: 38850014
• Citations: 16
• Influential citations: 1
• Summary: This article reviews and discusses TTR mutagenesis and amyloidogenesis, and their implications in disease onset, and compiles the various in vitro TTR aggregation protocols currently in use for research and drug development purposes.
• Evidence snippets:
• Snippet 1 (score: 0.447) > Protein aggregation and amyloid formation contribute to several debilitating diseases collectively known as Amyloidosis [1]. To date, more than fifty amyloid diseases have been identified, including localized amyloidosis found in neurodegenerative conditions like Alzheimer's and Parkinson's diseases, and systemic amyloidosis such as transthyretin amyloidosis and lysozyme amyloidosis [1]. These pathologies result from mutations, post-translational modifications, or partial proteolysis, and by abnormal folding or unfolding events affecting approximately fifty different peptides/ proteins. These end up adopting non-native, misfolded conformations prone to aggregate into highly ordered soluble oligomers and insoluble fibrils with a characteristic cross-β structure -the amyloid substance. Generally, amyloid diseases are not a consequence of the loss of function of the native protein but result from the cytotoxic nature of the amyloid aggregates and/or the action of amyloid fibrils on inter-cellular communication and tissue physiology. Although most amyloids are found extracellularly, amyloid-like deposits are also found inside cells [1]. > Transthyretin amyloid disorders include sporadic age-related wild-type TTR amyloidosis (ATTRwt), hereditary TTR amyloidosis polyneuropathy (ATTRv-PN), hereditary TTR amyloidosis cardiomyopathy (ATTRv-CM), hereditary leptomeningeal TTR amyloidosis (ATTRv-LM) and hereditary ocular TTR amyloidosis (ATTRv-OC). Although some of the ATTR clinical manifestations have unmet medical needs, in the last decade several disease-modifying therapies have contributed to slowing down disease progression and, in some cases, have ameliorated disease symptoms. The continuing efforts to better understand the molecular mechanisms of disease progression and tissue specificity are critical for the rational development of new and improved therapies for the treatment of TTR amyloidoses.

[5] Modulation of the Mechanisms Driving Transthyretin Amyloidosis

• Authors: Filipa Bezerra, M. Saraiva, M. R. Almeida
• Year: 2020
• Venue: Frontiers in Molecular Neuroscience
• URL: https://www.semanticscholar.org/paper/c1e8e4cf5970a0ac939aeffc6db8d5dd475f9611
• DOI: 10.3389/fnmol.2020.592644
• PMID: 33362465
• PMCID: 7759661
• Citations: 38
• Influential citations: 1
• Summary: Transthyretin (TTR) amyloidoses are systemic diseases associated with TTR aggregation and extracellular deposition in tissues as amyloid. The most frequent and severe forms of the disease are hereditary and associated with amino acid substitutions in the protein due to single point mutations in the TTR gene (ATTRv amyloidosis). However, the wild type TTR (TTR wt) has an intrinsic amyloidogenic potential that, in particular altered physiologic conditions and aging, leads to TTR aggregation in...
• Evidence snippets:
• Snippet 1 (score: 0.433) > ATTR amyloidosis is an under-recognized disease which is characterized by extracellular deposition of TTR aggregates in several organs, being polyneuropathy and cardiomyopathy the major clinical manifestations. The mechanism by which the tetramer disassembles and aggregates into amyloid fibrils has been considered the main driver of the disease. However, TTR proteolysis, namely occurring in the cardiac tissue, as well as its modulation have been increasingly documented as fundamental for understanding the development and progression of ATTR amyloidosis. > Many therapeutic approaches have been suggested for the treatment of ATTR amyloidosis targeting different steps of the pathology. Those therapies include interventions from the synthesis of the TTR variants through liver transplant or gene silencing therapies, to TTR stabilization, inhibition of aggregation, disruption of amyloid fibrils and clearance of amyloid deposits. The main targets for intervention on TTR amyloid formation are summarized in Figure 2. Although some the available therapies are more efficient than others, it becomes increasingly evident that combination of different therapies may improve the therapeutic outcome. In this sense, it would be interesting to test TTR gene silencing therapies in combination with protein stabilizers or disruptors of pre-existing amyloid deposits. It is also important to obtain more efficient and targeted therapies specific to organ and tissues with limited drug access as is the case of the eye and brain, that are particularly relevant in some forms of the disease. Moreover, it is crucial to continue with studies that can contribute to a better understanding of the mechanisms involved in the disease, in particular, TTR proteolysis, which has been mainly valued in the case of ATTR-CM and, also at the extracellular level involving either interactions with components of the extracellular matrix or with molecular and chemical chaperones acting as disease modulators. > Overall, detailed knowledge of the mechanisms of amyloid formation and the availability of different approaches allows directed and personalized interventions aiming higher specificity and efficacy of chosen therapeutic solutions.

[6] Neuroprotective Function of Non-Proteolytic Amyloid-β Chaperones in Alzheimer’s Disease

• Authors: Bhargy Sharma, K. Pervushin
• Year: 2019
• Venue: Amyloid Diseases
• URL: https://www.semanticscholar.org/paper/966e3e024e09b5c9bf4c6967acd39639d1a542fc
• DOI: 10.5772/INTECHOPEN.84238
• Citations: 2
• Summary: This chapter focuses on structural and morphological changes during aggregation of amyloids which have been identified using Nuclear magnetic resonance spectroscopy, X-ray crystallography, Electron microscopy, Atomic force microscopy and other biophysical techniques as well as interactions between chaperone proteins and amyloid moieties.
• Evidence snippets:
• Snippet 1 (score: 0.425) > Abnormal deposition of amyloids or "Amyloidosis" is hallmark of several chronic cerebrovascular diseases including neurodegeneration culminating into dementia. Efforts to develop targeted drugs against amyloids have been hindered since there is no universal mechanism that leads to protein misfolding or aggregation, and the aggregates usually do not correspond directly to clinical symptoms of the diseases. A clearer understanding of molecular interactions of amyloids can drive the ongoing therapeutic efforts to prevent aggregation of nascent amyloids into pathological species and to design timely interventions. In addition to aging, precursor mutations in genes and proteins, gene multiplication, expansion of amyloidogenic sequences, and xenobiotics such as air pollutants are risk factors usually associated with amyloidosis disorders [1]. There are different amyloidogenic species causing a variety of neuropathic diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Poly-glutamine disorders like Huntington disease (HD), Prion diseases including Creutzfeldt-Jakob disease, Lewy body disease, Amyotrophic Lateral Sclerosis (ALS) as well as metabolic diseases such as type II diabetes (T2D) and corneal dystrophy to name a few [2]. AD is a pandemic form of dementia caused due to improper aggregation of amyloidogenic proteins-amyloid-β (Aβ), which is a cleavage product of amyloid precursor protein (APP) and tau, stabilizes microtubules in neurons [3]. Prognosis is also closely associated with aggregation of α-Synuclein (αS) protein into Lewy bodies usually concentrated in presynaptic terminals [4]. Human islet amyloid polypeptide (IAPP), also known as amylin, is secreted along with insulin from pancreatic β-islet cells. IAPP rich amyloid plaques, facilitated by insulin resistance, are hallmarks of T2D [5]. β-sheeted infectious isoform of cellular prion protein (PrP) causes transmissible spongiform encephalopathy (TSE), broadly known as prion disease [2]. > In this chapter, we review various structures and conformations attained by Aβ peptides during the process

[7] Arrhythmic Manifestations of Cardiac Amyloidosis: Challenges in Risk Stratification and Clinical Management

• Authors: N. Laptseva, V. Rossi, I. Sudano, Rahel Schwotzer, F. Ruschitzka et al.
• Year: 2023
• Venue: Journal of Clinical Medicine
• URL: https://www.semanticscholar.org/paper/bfbf1950ad68a4aff16d3b2163345380608c3ddf
• DOI: 10.3390/jcm12072581
• PMID: 37048664
• PMCID: 10095126
• Citations: 19
• Influential citations: 3
• Summary: A deepened insight is given into the arrhythmic features of cardiac amyloidosis by discussing the pathogenesis of these arrhythmias, addressing the challenges in risk stratification and strategies for management in these patients.
• Evidence snippets:
• Snippet 1 (score: 0.424) > Amyloidosis is a systemic disease that is characterized by extracellular deposits of an insoluble fibrillar protein called amyloid within various tissues and organs, mainly the heart, kidneys and the peripheral nervous system [1]. There are more than 30 amyloidogenic precursor proteins in humans. The clinical phenotype depends on the nature of the amyloid and stage of disease, and can vary considerably in different patients. Cardiac amyloidosis is a frequent feature of the disease (in up to 60% of patients), causing a progressive, restrictive type of cardiomyopathy, and is associated with adverse clinical outcomes [2,3]. > There are two main forms of amyloidosis that significantly affect the heart: light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) [4,5]. The two forms have a completely different pathophysiology and their treatment differs considerably [6,7]. AL type is caused by overproduction and misfolding of antibody light chain fragments by an underlying clonal plasma cell in the bone marrow. Other vital organs may also be involved in AL amyloidosis, such as kidneys, liver, peripheral and autonomic nervous system. The majority of the patients are male and over the age of 50, although the disease may also occur in younger patients. Early diagnosis of AL cardiac amyloidosis is very important since the disease, if untreated, typically progresses rapidly and causes severe heart failure (HF), life-threatening arrhythmias, and results in death. ATTR, which occurs due to deposits of misfolded monomers of transthyretin (a small molecule mainly produced by the liver) can be observed either as a genetic disease (variant ATTR, or vATTR) or more commonly as a nonhereditary disease, called wild-type ATTR (wtATTR). In general, progression of ATTR cardiac amyloidosis (especially wtATTR) is slower as compared to that observed in AL cardiac amyloidosis, and untreated affected individuals may live many years after initial manifestation of disease. > The typical clinical presentation in patients with cardiac amyloidosis is HF with preserved ejection fraction (HFpEF).

[8] Alzheimer's disease mechanisms in peripheral cells: Promises and challenges

• Authors: E. Trushina
• Year: 2019
• Venue: Alzheimer's & Dementia : Translational Research & Clinical Interventions
• URL: https://www.semanticscholar.org/paper/43207b6874701048ebc4e950e37122fa446f16a5
• DOI: 10.1016/j.trci.2019.06.008
• PMID: 31720366
• PMCID: 6838468
• Citations: 29
• Influential citations: 3
• Summary: Development of efficacious therapeutic interventions for Alzheimer's disease is hampered by the lack of understanding early disease mechanisms, biomarkers, and models that mimic complex pathophysiology of human disease.
• Evidence snippets:
• Snippet 1 (score: 0.422) > Alzheimer's disease (AD) is the leading form of dementia where underlying molecular mechanisms are poorly understood. Therapeutic strategies designed to reduce levels of amyloid beta (Ab) plaques or hyperphosphorylated tau (ptau) containing tangles, two hallmarks of AD, have failed in clinical trials [1][2][3]. Factors contributing to this failure include limited understanding of early disease mechanisms and associated biomarkers, and poor translation of preclinical research conducted in model organisms [4,5]. Familial AD (FAD) accounts for~5% of all cases and is linked to mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes [6]. Most AD cases are sporadic late-onset AD (LOAD) with age being the greatest risk factor [6]. Recent clinical investigations using systems biology approaches and imaging techniques suggest that AD is a complex disorder where changes in multiple pathways occur years before the onset of clinical symptoms [7]. Moreover, the disease differentially affects males and females presenting additional challenges for biomarker and drug discovery [8]. Animal models currently used for preclinical therapeutic development do not recapitulate the complexity of sporadic AD. Thus, there is an urgent need to identify translational models that better represent AD mechanisms and could complement existing animal models to test novel therapeutic approaches and develop panels of disease stage-and sex-specific diagnostic and prognostic biomarkers. > This article aims to test the hypothesis that AD is a systemic disorder where peripheral cells recapitulate major molecular mechanisms affected in the brain. The hypothesis predicts that alterations in pathways shown fundamentally important in the etiology of AD including inflammation, abnormal calcium signaling, amyloid precursor protein processing, Ab and p-tau accumulation, altered oxidative metabolism, mitochondrial dysfunction, and abnormal cellular energetics will be detected in peripheral cells and biofluids of AD patients providing a unique opportunity to study/ manipulate these mechanisms in a contest of the individuals' genetic, epigenetic, and metabolic background. Here, we will (1) provide the rationale for this hypothesis reviewing evidence that peripheral cells and biofluids recapitulate mechanisms affected in the brain; (2) discuss opportunities

[9] The AL Amyloid Fibril: Looking for a Link between Fibril Formation and Structure

• Authors: Christian Haupt
• Year: 2021
• Venue: Hemato
• URL: https://www.semanticscholar.org/paper/4d1c46c8467ff75e1f0e5ce51f2d67b5cc6c3824
• DOI: 10.3390/hemato2030032
• Citations: 7
• Summary: Recent biochemical and biophysical studies that have expanded knowledge on how versatile the structure of AL fibrils in patients is are reviewed and highlighted their implications for the molecular mechanism of fibril formation in AL amyloidosis are highlighted.
• Evidence snippets:
• Snippet 1 (score: 0.415) > The formation and deposition of fibrils derived from immunglobulin light chains is a hallmark of systemic AL amyloidosis. A particularly remarkable feature of the disease is the diversity and complexity in pathophysiology and clinical manifestations. This is related to the variability of immunoglobulins, as virtually every patient has a variety of mutations resulting in their own unique AL protein and thus a unique fibril deposited in the body. Here, I review recent biochemical and biophysical studies that have expanded our knowledge on how versatile the structure of AL fibrils in patients is and highlight their implications for the molecular mechanism of fibril formation in AL amyloidosis.

[10] Are we creating a new phenotype? Physiological barriers and ethical considerations in the treatment of hereditary transthyretin-amyloidosis

• Authors: Maike F. Dohrn, J. Medina, K. Olaciregui Dague, E. Hund
• Year: 2021
• Venue: Neurological Research and Practice
• URL: https://www.semanticscholar.org/paper/74e5dd6052df6b49203e21d721efd832f467d2c8
• DOI: 10.1186/s42466-021-00155-8
• PMID: 34719408
• PMCID: 8559355
• Citations: 18
• Summary: The current advances in treating ATTRv amyloidosis have become a meaningful example for mechanism-based treatment and will still have to face new challenges including shifts in the phenotype spectrum and the ongoing need for improved treatment precision.
• Evidence snippets:
• Snippet 1 (score: 0.414) > Hereditary transthyretin (TTR) amyloidosis (ATTRv) is an autosomal dominant, systemic disease transmitted by amyloidogenic mutations in the TTR gene. To prevent the otherwise fatal disease course, TTR stabilizers and mRNA silencing antisense drugs are currently approved treatment options. With 90% of the amyloidogenic protein produced by the liver, disease progression including polyneuropathy and cardiomyopathy, the two most prominent manifestations, can successfully be halted by hepatic drug targeting or—formerly—liver transplantation. Certain TTR variants, however, favor disease manifestations in the central nervous system (CNS) or eyes, which is mostly associated with TTR production in the choroid plexus and retina. These compartments cannot be sufficiently reached by any of the approved medications. From liver-transplanted patients, we have learned that with longer lifespans, such CNS manifestations become more relevant over time, even if the underlying TTR mutation is not primarily associated with such. Are we therefore creating a new phenotype? Prolonging life will most likely lead to a shift in the phenotypic spectrum, enabling manifestations like blindness, dementia, and cerebral hemorrhage to come out of the disease background. To overcome the first therapeutic limitation, the blood–brain barrier, we might be able to learn from other antisense drugs currently being used in research or even being approved for primary neurodegenerative CNS diseases like spinal muscular atrophy or Alzheimer’s disease. But what effects will unselective CNS TTR knock-down have considering its role in neuroprotection? A potential approach to overcome this second limitiation might be allele-specific targeting, which is, however, still far from clinical trials. Ethical standpoints underline the need for seamless data collection to enable more evidence-based decisions and for thoughtful consenting in research and clinical practice. We conclude that the current advances in treating ATTRv amyloidosis have become a meaningful example for mechanism-based treatment. With its great success in improving patient life spans, we will still have to face new challenges including shifts in the phenotype spectrum and the ongoing need for improved treatment precision. Further investigation is needed to address these closed barriers and open questions.

[11] Tissue Characterization in Cardiac Amyloidosis

• Authors: V. Musetti, F. Greco, V. Castiglione, A. Aimo, C. Palmieri et al.
• Year: 2022
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/e42701c0e211d214f44aa633a34d8719838c3109
• DOI: 10.3390/biomedicines10123054
• PMID: 36551810
• PMCID: 9775200
• Citations: 17
• Influential citations: 2
• Summary: The present review focuses on the status of tissue characterization in cardiac amyloidosis, from histochemistry to immunohistochemistry and mass spectrometry, as well as on its future directions.
• Evidence snippets:
• Snippet 1 (score: 0.412) > Amyloidoses are characterized by the extra-cellular deposition of amyloidogenic proteins in a cross-β-sheet structure that confers a typical green birefringence by Congo red staining under polarized light microscopy [1]. The tissue deposition of amyloid may lead to organ failure [1,2]. Cardiac amyloidosis (CA) has long been considered a rare disease [1,3]; however, recent advances in non-invasive diagnostic tools have led to a reconsideration of the epidemiology of the disease. Furthermore, the new therapeutic strategies available have increased the clinical impact of CA diagnosis [4][5][6][7][8]. > More than 30 amyloidogenic proteins have been identified so far, with immunoglobulin light chains and transthyretin (TTR) being the most common amyloidogenic precursors of CA, respectively reasonable for AL and ATTR amyloidosis [9,10]. AL amyloidosis is a systemic disease involving almost every organ and has a poor prognosis, particularly when the heart is affected [11]. Two major forms of ATTR amyloidosis are recognized: wild-type ATTR (ATTRwt) and variant ATTR (ATTRv; due to point mutations in the TTR gene) amyloidosis [12,13]. In CA, the myocardial damage and the functional impairment are related to the type of the amyloidogenic protein as well as to the pattern and the extension of the amyloid deposits [11]. Recent investigations have also identified other mechanisms, including fibrosis and inflammatory pathways, which may play a significant role in myocardial dysfunction [14,15]. Amyloid typing is crucial for the clinical management of affected patients, since the misidentification of the amyloidogenic protein can lead to inappropriate treatments [7,16]. In some cases, particularly in ATTR amyloidosis, a non-biopsy diagnosis can be obtained; nevertheless, tissue characterization is always needed when a plasma cell dyscrasia is present and/or when nuclear medicine findings are inconclusive [17][18][19].

[12] Gelsolin pathogenic Gly167Arg mutation promotes domain-swap dimerization of the protein

• Authors: F. Bonì, M. Milani, A. Barbiroli, L. Diomede, E. Mastrangelo et al.
• Year: 2017
• Venue: Human Molecular Genetics
• URL: https://www.semanticscholar.org/paper/02e035ff678ddb449cb65f97c28e695ddc1a77a5
• DOI: 10.1093/hmg/ddx383
• PMID: 29069428
• PMCID: 5886171
• Citations: 18
• Summary: Structural and biophysical characterizations reveal that the Gly167Arg mutation alone is responsible for the monomer to dimer transition and that, even in the context of the full-length protein, the pathogenic variant is prone to form dimers.
• Evidence snippets:
• Snippet 1 (score: 0.408) > examples in (16)(17)(18)], in kindred lacking Finnish ancestors, suggesting that this disease, owing to its neglected state and complex and variable clinical picture, has often been un/ misdiagnosed. > Two novel pathological variants of gelsolin have recently been described to be associated with renal amyloidosis containing the following mutations: Asn184 to Lys and Gly167 to Arg (C633 to A and G580 to A, respectively) (19)(20)(21). In addition, a sporadic form of AGel with marked wild-type (wt) gelsolin deposits surrounding a sellar glioma of the hypophysis has also recently been discovered (22). This finding is particularly relevant since, in several clinical reports of pituicytoma-associated amyloidosis (23)(24)(25), it is the first one in which the etiological agent, i.e. the main constituent of the aggregates, was identified. Therefore, AGel can be classified into three different forms according to the nature of the protein, mutants or wt, in addition to the organ(s) involved in fibril deposition: (i) systemic (or Finnish-type), (ii) kidney localized and (iii) sporadic. > All AGel types share the lack of apt pharmacological therapies that cure the disease, targeting the source of toxicity, rather than only acting as palliative, symptomatic treatments. However, the use of nanobodies raised against mutated gelsolin recently showed great potential as a novel strategy against AGel, both in vitro and in vivo exploiting adeno-associated viruses (26)(27)(28). Dissection of the molecular bases that lead to wt and mutant gelsolin misfolding, and knowledge of the mechanisms underlying each AGel form, are crucial to identify pharmacologically relevant targets and to develop effective therapeutic strategies. > With the exception of our recent description of the underlying molecular bases of Asn184Lys amyloidosis (29), little is known about the pathological mechanisms that lead to renal or sporadic forms. On the contrary, the amyloidogenic pathway of the systemic Asp187

[13] Oxidative Stress, Chronic Inflammation, and Amyloidoses

• Authors: A. Orzechowski, A. Cywińska, A. Rostagno, F. Rizzi
• Year: 2019
• Venue: Oxidative Medicine and Cellular Longevity
• URL: https://www.semanticscholar.org/paper/b1edc328b4cf156216b002e11396f08538bd4fb2
• DOI: 10.1155/2019/6024975
• PMID: 31612076
• PMCID: 6755281
• Citations: 11
• Summary: Department of Physiological Sciences, Warsaw University of Life Sciences (SGGW), Nowoursynowska 159, 02-776 Warsaw, Poland Department of Pathology and Veterinary Diagnostics, Warsaw Universitas degli Studi di Parma, Via Volturno 39/E, Parma.
• Evidence snippets:
• Snippet 1 (score: 0.408) > Amyloid diseases are part of an emerging complex group of chronic and progressive entities collectively known as disorders of protein folding. For reasons still under active investigation, soluble proteins normally found in interstitial or biological fluids change their conformation and form poorly soluble molecular assemblies that accumulate as extracellular fibrillar aggregates within the parenchyma and blood vessels of different organs. Once formed, these amyloid fibrils that typically exhibit a β-sheet-rich secondary structure are highly resistant to proteolytic degradation, a characteristic that impairs their effective physiologic removal and leads to their tissue accumulation inducing local hypoxia and cellular damage with overall organ dysfunction and, eventually, death. > The molecular pathogenic mechanisms associated with amyloid diseases are complex and involve cross-talk among different cell populations and cellular pathways. Mounting evidence points out to inflammation-related mechanisms and oxidative stress as associated burden for amyloidosis. In spite of multiple studies, it still remains to be elucidated whether oxidative stress is a key contributor to the disease pathogenesis and progression or whether-on the contrary-it is a mere consequence of the cellular responses elicited by the presence of amyloid deposits and the concomitant inflammatory processes affecting injured tissue. This special issue provides an updated view on the role of oxidative stress and inflammation-related cellular pathways to the etiopathogenesis, progression, and treatment strategies of amyloid diseases. > One of the papers of this special issue, "Hypoxia and Inflammation as a Consequence of β-fibril Accumulation: A Perspective View for New Potential Therapeutic Targets," addresses the link between local hypoxia and the induction of chronic long-lasting inflammation in the context of the tissue accumulation of the β-sheet-rich amyloid deposits. The authors propose that the induction of cell death mechanisms in conjunction with local tissue hypoxia associated with the amyloid accumulation constitutes important events for the pathogenesis and progression of amyloidosis. The authors hypothesize that molecules released by necrotic cells activate inflammatory responses through Damage-Associated Molecular Patterns (DAMPs) and evoke activation of HIF-1α/NF-κB-dependent pathways suggesting that modulation of these cellular paths may constitute new therapeutic strategies. Another manuscript of the special issue focuses on

[14] Unusual Pain Disorders – What Can Be Learned from Them?

• Authors: J. Sachau, D. Kersebaum, R. Baron, A. Dickenson
• Year: 2021
• Venue: Journal of Pain Research
• URL: https://www.semanticscholar.org/paper/11a1bceba8d0d4afec7cc632571f8f6d014c648d
• DOI: 10.2147/JPR.S287603
• PMID: 33758536
• PMCID: 7980038
• Citations: 3
• Influential citations: 1
• Summary: Pain therapists and researchers should be aware of these rare and unusual pain disorders as they offer the unique opportunity to study mechanisms, identify new druggable targets and finally because early diagnosis might save many patient lives.
• Evidence snippets:
• Snippet 1 (score: 0.408) > In the past, systemic transthyretin (ATTR) amyloidosis was classified as a poorly or completely untreatable, rapidly progressive disease.Painful polyneuropathy is an early symptom that significantly reduces the quality of life in the affected patients.Extensive research within the last years has led to the identification of new -also non-invasive -diagnostic tools and promising therapeutic options to improve the overall treatment of patients, making it critical and relevant to raise awareness of this disease. > Systemic ATTR amyloidosis results from 1) a mutation causing a change in the TTR protein structure, ie hereditary ATTR (ATTRv) amyloidosis or 2) a process during ageing, ie wild-type ATTR (ATTwt) amyloidosis.Physiologically, transthyretin (TTR) acts as a carrier protein to transport thyroxin and retinol (vitamin A) via associating with its binding protein and is mostly synthesized by the liver.In ATTR amyloidosis, the TTR protein loses its stable tetrameric conformation, dissociates into monomers that are misfolded, aggregate and finally deposit as amyloid into tissues and organs (Figure 1). 43Since amyloid deposition can theoretically affect every organ, the clinical manifestation is very heterogenous.This clinical chameleon complicates the correct diagnosis resulting in delayed start of therapy and hence rapid disease progression. > Pain is a common clinical symptom in ATTRv amyloidosis and led to the first description of the disease by Corino Andrade in 1952 who observed an increased incidence of a rapid progressive painful foot disease in families from north of Portugal, that was associated with symptoms of a peripheral neuropathy and a high mortality rate. 44In a study by Lozeron et al, pain was present in more than half of the patients with demyelinating ATTRv amyloid polyneuropathy. 45Different pathophysiological mechanisms have been proposed that lead to nerve fiber damage in ATTRv amyloidosis. 46

[15] Iatrogenic Dementia: Providing Insight into Transmissible Subtype of Alzheimer’s Disease, Creutzfeldt–Jakob Disease and Cerebral Amyloid Angiopathy

• Authors: Stella Karatzetzou, Serafeim Ioannidis, E. Konstantinopoulou, D. Parisis, Theodora Afrantou et al.
• Year: 2025
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/24ab859dfee1209eeecb40472a4c291945fcadee
• DOI: 10.3390/biom15040522
• PMID: 40305264
• PMCID: 12025122
• Summary: The present review aims to explore the distinct features of acquired dementia encompassing a history of potential exposure and relatively early age of onset, highlighting transmission potential with a rather prion-like pattern.
• Evidence snippets:
• Snippet 1 (score: 0.406) > An extensive literature review was conducted in order to elucidate the transmission potential of dementia in a clinical setting of a neurodegenerative disease. Original articles dealing with the underlying pathomechanisms and the distinct clinical phenotype of acquired type of cognitive decline were identified and reviewed. > Proteinopathies represent a group of diseases characterized by the deposition of misfolded protein aggregates. These abnormally accumulated proteinaceous structures in the brain can trigger the pathological cascade that leads to neurologic dysfunction and subsequently to clinically evident neurodegeneration with manifestations within the dementia spectrum. Prion proteins, Aβ and tau being among them, stand for the pathological hallmarks of various neurodegenerative diseases, reflecting the main underlying pathomechanisms [62]. > In an attempt to explore the underlying molecular pathways involved in iatrogenically triggered amyloidogenesis, Bonilauri [71] proposed a classification of relevant cases according to the nature of medical intervention and subsequent impact on amyloid proteins. As far as neurodegenerative disorders including AD, CAA and CJD are concerned, the amyloidogenic cascade can be initiated by the transmission of amyloid oligomers and fibrils through different medical procedures. Already found in a pre-existing amyloid state in cases of organ/tissue transplantation or contaminated instruments, amyloid seeds may enhance and ultimately accelerate the formation of insoluble mature amyloid fibrils, thus disrupting normal tissue functionality and leading to a wide range of clinical manifestations. According to growing experimental evidence, the ability of misfolded proteins to continuously induce the conversion of similar physiological proteins into a pathological form through seeding is a characteristic feature not only of prion protein but also Aβ, tau and a-synuclein [10]. A common molecular mechanism seems to be responsible for the replication and spread of these different misfolded protein aggregates within the central nervous system [3]. > It is of great interest that a-synuclein might exhibit at least some of the misfolded protein properties, including the generation of a-synuclein aggregates that act as a template for the formation of seeds, propagation between cells and spread across certain anatomical pathways.

[16] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

• Authors: Hao Xiong, Jinsheng Guo
• Year: 2025
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
• DOI: 10.3390/ph18040507
• PMID: 40283943
• PMCID: 12030350
• Citations: 8
• Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
• Evidence snippets:
• Snippet 1 (score: 0.402) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[17] Structural Basis for Vital Function and Malfunction of Serum Amyloid A: an Acute-Phase Protein that Wears Hydrophobicity on Its Sleeve

• Authors: O. Gursky
• Year: 2020
• Venue: Current Atherosclerosis Reports
• URL: https://www.semanticscholar.org/paper/1c041f2c08905510171a02b26816bb26f11bd435
• DOI: 10.1007/s11883-020-00888-y
• PMID: 32968930
• PMCID: 7511256
• Citations: 28
• Summary: Recent advances in understanding of the structure-function relationship of SAA are summarized, its newly emerging beneficial roles in lipid transport and inflammation control are outlined, and factors that critically influence its misfolding in AA amyloidosis are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.402) > The major therapies for AA amyloidosis target the underlying inflammatory disease and include antibacterial, anti-inflammatory, and immunosuppressive drugs; dialysis and kidney transplant are used to treat advanced renal damage. The drugs reduce SAA levels, which reduces the amyloid load and reverses the disease. However, factors other than amyloid load can also contribute to clinical symptoms [91], and the existing treatments are not always efficient [92]. For example, antiinflammatory approaches are unsuited for patients with idiopathic AA amyloidosis without the underlying chronic inflammation [3•, 93], necessitating the development of new therapies. > Some therapeutic approaches target the protein misfolding pathway. This includes interactions with GAGs, particularly heparan sulfate, that dissociate SAA from HDL and accelerate fibrillogenesis [83,94]. Sulfonated or sulfated GAG mimetics were proposed to block SAA-GAG interactions. Unfortunately, a sulfonated small molecule drug eprodisate failed to show efficiency in phase-3 clinical trials and was discontinued in 2016 (ClinicalTrials.gov Identifier: NCT01215747). > Other approaches propose to block amyloidogenic segments of SAA by using complementary peptides [95] or lipids. In particular, decreasing triglyceride levels in the core of HDL helps retain SAA and other apolipoproteins on the HDL surface and thereby retard fibrillogenesis [96]. If so, existing triglyceride-lowering therapies hold promise for treating AA amyloidosis, including cases without the underlying inflammation. Conversely, increased plasma triglycerides are expected to augment AA amyloidosis. This idea is consistent with clinical studies reporting a direct correlation between idiopathic AA amyloidosis and obesity, a condition wherein plasma triglycerides are elevated [93,97]. > Another proposed approach uses a cell-based system to identify nontoxic inhibitors of SAA fibrillogenesis regardless of specific mechanisms of action [98]. This approach targets the protein quality control cellular machinery and has a high screening capability, which helps select candidates for future animal model studies.

[18] Familial Mediterranean Fever: Assessing the Overall Clinical Impact and Formulating Treatment Plans

• Authors: D. Rigante, R. Manna
• Year: 2019
• Venue: Mediterranean Journal of Hematology and Infectious Diseases
• URL: https://www.semanticscholar.org/paper/3675c7536975c9ceacb1d96eb667a053c06d0fc7
• DOI: 10.4084/MJHID.2019.027
• PMID: 31205631
• PMCID: 6548206
• Citations: 50
• Influential citations: 2
• Summary: Colchicine, a tricyclic alkaloid with anti-microtubule and anti-inflammatory properties, is the bedrock of FMF management: daily administration of colchicines prevents the recurrence ofFMF attacks and the development of secondary AA amyloidosis.
• Evidence snippets:
• Snippet 1 (score: 0.396) > 112 Diagnosis of FMF is mainly made on the basis of the typical clinical findings in association with the peculiar ethnicity, family history, and response to colchicine.113,114 Despite the great steps in our understanding of FMF, we still have a number of hanging questions: for instance, what is the exact role of additional genes in the definition of the final FMF phenotype, what is the pathophysiology of the disease in patients with only one MEFV mutation or in those without any MEFV mutation, which are further unexplored inflammatory pathways which might be involved in the disease expression or progression to amyloidosis, and so on.The progress in the knowledge of genetic determinants of FMF could constitute a significant step towards the understanding of the human genome power and general mechanisms of inflammation with future relevant therapeutic implications. Wier awareness of FMF will probably reduce the diagnostic delay in recognition of the disease and positively affect the quality of life of patients who will have a lower risk of long-term morbidity and complications.

[19] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

• Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
• Year: 2020
• Venue: Current Neuropharmacology
• URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
• DOI: 10.2174/1570159X17666191021141057
• PMID: 31631822
• PMCID: 7327943
• Citations: 12
• Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
• Evidence snippets:
• Snippet 1 (score: 0.391) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[20] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.390) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.

ADan Amyloidosis (Familial Danish Dementia) — Comprehensive Disease Characteristics Report

Executive summary

ADan amyloidosis is a rare, autosomal dominant, Mendelian neurodegenerative disorder historically described in a Danish pedigree and commonly referred to as familial Danish dementia (FDD) or heredopathia ophthalmo‑oto‑encephalica. It is caused by a pathogenic stop-region duplication in ITM2B (BRI2) that creates an extended precursor protein (277 aa) and a de novo 34–amino‑acid amyloidogenic peptide (ADan) produced by furin-like processing. The clinical syndrome classically begins with early cataracts, followed by progressive hearing loss, then cerebellar ataxia/tremor and later progressive dementia, accompanied by prominent cerebral and retinal amyloid angiopathy and tau neurofibrillary pathology. Recent (2023–2024) work has strengthened links between ITM2B/BRI2 biology and microglial pathways (including TREM2 processing/phagocytosis) and has quantitatively mapped sequence determinants of ADan amyloid nucleation. (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6, yin2024functionalbri2trem2interactions pages 1-2, arber2024microgliacontributeto pages 1-2, martin2024amyloids“atthe pages 3-5)

1. Disease information

1.1 What is the disease?

Familial Danish dementia (FDD) is a hereditary neurodegenerative disorder characterized by early ophthalmologic disease (cataracts), progressive hearing loss, cerebellar ataxia with tremor, and later progressive dementia. Neuropathology includes cerebral and retinal amyloid angiopathy with deposition of the ADan amyloid peptide (and often co-deposition of Aβ) and neurofibrillary tangles resembling Alzheimer-like tau pathology. (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6, rostagno2005chromosome13dementias pages 10-11)

1.2 Key identifiers (with availability constraints)

A curated disease mapping from OpenTargets identifies ADan amyloidosis as MONDO_0007297 and connects it to ITM2B with supporting literature PMIDs (e.g., PMID: 10391242; PMID: 10781099) in the association evidence. (OpenTargets Search: familial Danish dementia,ADan amyloidosis-ITM2B)

Other identifiers (OMIM, Orphanet, MeSH, ICD-10/ICD-11) were not directly retrieved in the current tool context; they are flagged as missing rather than inferred. (OpenTargets Search: familial Danish dementia,ADan amyloidosis-ITM2B)

Table: This table summarizes the key identifiers and accepted names for ADan amyloidosis based only on evidence retrieved in the current tool context. It is useful for mapping the disease entity across nomenclature systems while clearly flagging identifiers not yet directly retrieved.

1.3 Synonyms / alternative names

Common synonyms include: - Familial Danish dementia (FDD) (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6) - Heredopathia ophthalmo‑oto‑encephalica (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6) - “Chromosome 13 dementias” (category including familial British and Danish dementias) (rostagno2005chromosome13dementias pages 1-2)

1.4 Evidence provenance

Much clinical characterization derives from aggregated disease-level descriptions anchored in a multigenerational pedigree/case series (e.g., 13 cases across five generations) and from neuropathologic analyses of post-mortem tissue; mechanistic insights largely derive from animal models, iPSC-derived cell types, and in vitro systems. (rostagno2005chromosome13dementias pages 4-6, yin2024functionalbri2trem2interactions pages 1-2, todd2016oxidativestressand pages 11-13)

2. Etiology

2.1 Disease causal factors

Primary cause (genetic): FDD is caused by a 10-nucleotide duplication near the ITM2B/BRI2 stop codon (reported as 787_796dupTTTAATTTGT) producing a mutant 277-aa precursor (often described as p.Ser266PhefsTer11 / p.Ser266PhefsX11). Furin-like processing at the BRI2 C-terminus releases ADan, a 34-aa amyloidogenic peptide that deposits in brain and vessel walls. (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6, rostagno2005chromosome13dementias pages 2-4)

Two mechanistic classes are repeatedly discussed: 1) Toxic gain-of-function due to aggregation/accumulation of ADan (and ADan-associated CAA). (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6) 2) Loss-of-function due to reduced levels of functional mature BRI2 (mBRI2), impairing physiological roles at synapses and altering APP processing. (matsuda2011increasedaβppprocessing pages 4-5, yin2021danishandbritish pages 1-2)

Table: This table summarizes the currently supported genetic cause and pathogenic mechanism of ADan amyloidosis/familial Danish dementia from the retrieved evidence. It highlights the ITM2B Danish duplication, its processing into ADan, and the evidence for both toxic peptide accumulation and BRI2 loss-of-function.

2.2 Risk factors

Genetic: The causal ITM2B duplication is the principal risk factor; the disorder is autosomal dominant. (rostagno2005chromosome13dementias pages 4-6, choudhury2025pathologicalmechanismsof pages 1-2)

Environmental: No environment-specific risk factors were retrieved in this evidence set.

2.3 Protective factors

No definitive protective genetic or environmental factors were retrieved. However, mechanistic genetic modification in models (APP haplodeficiency) prevents synaptic/memory deficits, supporting APP-derived products as mediators of some phenotypes (this is not a population protective factor but a mechanistic modifier). (matsuda2011increasedaβppprocessing pages 4-5)

2.4 Gene–environment interactions

No gene–environment interaction evidence was retrieved.

3. Phenotypes

3.1 Core phenotype spectrum and characteristics

Clinical course described in reviews: - Cataracts often in the third decade (median visual symptom onset 27 years in a 13-case series). (rostagno2005chromosome13dementias pages 4-6) - Hearing loss typically 10–20 years after ocular symptoms, often severe by the fifth decade. (garringer2010modelingfamilialbritish pages 3-4) - Cerebellar ataxia with intention tremor in adulthood, progressive. (garringer2010modelingfamilialbritish pages 3-4, choudhury2025pathologicalmechanismsof pages 1-2) - Dementia probably beginning in the sixth decade, progressive and fatal. (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6) - Other reported features include psychosis and spastic paralysis/spasticity in review literature. (rostagno2005chromosome13dementias pages 10-11)

Table: This table summarizes the major clinical and pathologic features reported for familial Danish dementia/ADan amyloidosis, including approximate timing and suggested HPO mappings. It is useful for disease knowledge-base curation and phenotype annotation.

3.2 Quality-of-life impact

While formal QoL instruments were not retrieved, the phenotype timing suggests a substantial, staged disability burden driven by early visual impairment, progressive deafness, gait/motor dysfunction, and eventual dementia requiring comprehensive supportive care. (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6)

4. Genetic / molecular information

4.1 Causal gene

• ITM2B (BRI2) encodes a type II transmembrane glycoprotein with a BRICHOS domain and undergoes furin processing at a C-terminal site (…KGIQKR243↓E244…). (rostagno2005chromosome13dementias pages 2-4)

4.2 Pathogenic variant and functional consequence

• Danish FDD duplication creates an extended precursor and generates ADan (34 aa). (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6)
• In knock-in mouse models of Danish/British dementias, pathogenic ITM2B mutations reduce BRI2 protein stability/maturation, lowering functional mature BRI2 at synapses and producing synaptic physiology abnormalities consistent with loss of function. (yin2021danishandbritish pages 1-2)

4.3 Modifier pathways and intersecting biology

APP processing / Aβ: In one human FDD brain compared with one control, APP/Aβ metabolites were markedly increased (e.g., soluble Aβ42 11×, insoluble Aβ42 125×). These data support a mechanistic link between BRI2 loss-of-function and increased APP processing/Aβ burden, though human sample size was extremely limited in the retrieved evidence. (matsuda2011increasedaβppprocessing pages 4-5)

Microglia / TREM2 (recent development, 2024): BRI2 interacts with TREM2 and inhibits TREM2 processing. In Bri2 loss-of-function contexts, TREM2-CTF and soluble sTREM2 are elevated, and microglial phagocytosis is reduced—supporting BRI2 as a microglial regulatory node relevant to AD and ITM2B-associated dementias. (yin2024functionalbri2trem2interactions pages 1-2)

5. Environmental information

No specific environmental, lifestyle, toxin, or infectious triggers were identified in the retrieved evidence.

6. Mechanism / pathophysiology

6.1 Causal chain (integrated current understanding)

1) ITM2B Danish duplication → extended BRI2 precursor (277 aa) (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6) 2) Furin-like cleavage near residue 243/244 → release of ADan 34-mer (rostagno2005chromosome13dementias pages 2-4, rostagno2005chromosome13dementias pages 4-6) 3) ADan misfolding/aggregation and deposition predominantly in vessels (CAA, including retinal vasculature) with frequent co-deposition of Aβ (rostagno2005chromosome13dementias pages 4-6, matsuda2011increasedaβppprocessing pages 4-5) 4) Downstream neurodegenerative cascades: vascular dysfunction/BBB leakage and neuroinflammation (rat KI model), oxidative stress/mitochondria-mediated apoptosis (cell models), synaptic dysfunction and altered neurotransmission (KI models), and tau neurofibrillary pathology. (choudhury2025pathologicalmechanismsof pages 1-2, todd2016oxidativestressand pages 11-13, yin2021danishandbritish pages 1-2, garringer2010modelingfamilialbritish pages 3-4)

6.2 Oxidative stress and mitochondria-mediated apoptosis (cell models)

In differentiated SH-SY5Y cells, pyroglutamate-modified ADan (ADan pE) triggers rapid ROS generation and intrinsic apoptosis markers including cytochrome c release, loss of mitochondrial membrane potential, and caspase-3 activation. An abstract-supported mechanistic statement from the paper includes that “ADan pE provoked DNA fragmentation after only 8 hour peptide challenge” and that “ADan pE treatment caused the release of cyt c…” with loss of mitochondrial membrane potential. (todd2016oxidativestressand pages 11-13, todd2016oxidativestressand pages 13-14)

Intervention evidence in vitro: the antioxidant Trolox reduced ROS-linked caspase-3 activation, and an ADan C-terminal monoclonal antibody (1B7) “completely neutralize[d] ADan-mediated cytotoxicity,” supporting oxidative stress and ADan sequence-specific toxicity as targetable processes (preclinical). (todd2016oxidativestressand pages 13-14, todd2016oxidativestressand pages 11-13, todd2016oxidativestressand pages 14-16)

Visual evidence (figures): Todd et al. show cytochrome c redistribution and Trolox-sensitive caspase-3 activation in figure panels. (todd2016oxidativestressand media f315265f, todd2016oxidativestressand media d7873ce6)

6.3 Synaptic dysfunction and glutamatergic transmission (KI models)

In Danish and British dementia knock-in mice, spontaneous glutamate release and AMPAR-mediated responses are decreased while short-term synaptic facilitation is increased, resembling Itm2b knockout phenotypes and supporting a BRI2 loss-of-function contribution. (yin2021danishandbritish pages 1-2)

6.4 Microglia, innate immunity, and TREM2 (2023–2024)

Recent work highlights cell-type specificity: - ITM2B expression is ~34-fold higher in microglia than neurons and ~15-fold higher than astrocytes in iPSC-derived models, and ABri peptide is detectable in patient iPSC-microglia lysates/conditioned media (British dementia), suggesting microglia can be a major cellular source of ITM2B-derived amyloid peptides; the mechanism is relevant to ADan generation because both ABri and ADan derive from ITM2B stop-region mutations and furin cleavage. (arber2024microgliacontributeto pages 1-2, arber2023microgliaproducethe pages 1-4) - In 2024 EMBO Reports, BRI2 directly interacts with TREM2 and inhibits its processing; Bri2 deletion reduces microglial phagocytosis, suggesting innate immune dysfunction as a convergent mechanism relevant to ITM2B dementias and AD. (yin2024functionalbri2trem2interactions pages 1-2)

6.5 Sequence-level determinants of ADan amyloid nucleation (2024)

A 2024 deep mutagenesis/random extension study provides quantitative mapping of the ADan amyloid core: ADan showed strong nucleation in a yeast-based assay (25.14 ± 3.41% growth; ~2× Aβ42), while ABri was essentially non-nucleating in that assay. The authors map a putative core region between residues 20–26 (L20–F26) and quantify mutation effects on nucleation, supporting the concept that stop-loss extensions can generate de novo amyloid motifs. (martin2024amyloids“atthe pages 3-5)

Suggested ontology terms (examples)

• GO biological processes: amyloid fibril formation; regulation of APP processing; oxidative stress response; mitochondrial outer membrane permeabilization; intrinsic apoptotic signaling; microglial phagocytosis; regulation of TREM2 processing. (matsuda2011increasedaβppprocessing pages 4-5, yin2024functionalbri2trem2interactions pages 1-2, todd2016oxidativestressand pages 13-14)
• CL cell types: microglia (CL:0000129); neurons; astrocytes; vascular smooth muscle cells; endothelial cells. (rostagno2005chromosome13dementias pages 1-2, arber2024microgliacontributeto pages 1-2)

7. Anatomical structures affected

7.1 Organ/tissue systems

• Eye (lens/retina): early cataracts and retinal amyloid angiopathy. (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6)
• Central nervous system: cerebellum (ataxia; subpial/leptomeningeal vascular pathology in models), hippocampus (tangles; cognitive impairment), widespread cerebral vasculature (CAA). (rostagno2005chromosome13dementias pages 4-6, choudhury2025pathologicalmechanismsof pages 1-2, garringer2010modelingfamilialbritish pages 3-4)

7.2 Cell/tissue pathology

• Vascular walls and capillaries are prominent sites of amyloid deposition (CAA), with neuroinflammatory responses including activated microglia in proximity to deposits in models. (rostagno2005chromosome13dementias pages 4-6, garringer2010modelingfamilialbritish pages 6-7)

UBERON suggestions (examples): UBERON:0000955 brain; UBERON:0002037 cerebellum; UBERON:0002421 hippocampus; UBERON:0000970 retina; UBERON:0000965 lens. (rostagno2005chromosome13dementias pages 4-6, choudhury2025pathologicalmechanismsof pages 1-2)

8. Temporal development

• Onset pattern: insidious, chronic, progressive. Sensory manifestations precede neurodegeneration (cataracts → hearing loss → ataxia → dementia). (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6)
• Progression: progressive worsening over decades; median death in one pedigree series at 58 years. (rostagno2005chromosome13dementias pages 4-6)

9. Inheritance and population

9.1 Inheritance

Autosomal dominant inheritance is consistently reported in reviews and mechanistic summaries. (choudhury2025pathologicalmechanismsof pages 1-2, rostagno2005chromosome13dementias pages 4-6)

9.2 Epidemiology

No population prevalence/incidence estimates were retrieved in the current evidence set. The most concrete human aggregation in the retrieved evidence is a 13-case, five-generation pedigree-based series. (rostagno2005chromosome13dementias pages 4-6)

10. Diagnostics

10.1 Practical diagnostic approach (current evidence)

• Genetic confirmation: identify the ITM2B Danish duplication (c.787_796dupTTTAATTTGT) in the setting of compatible phenotype and family history. (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6)
• Neuropathology: predominance of cerebral and retinal amyloid angiopathy with ADan deposits, frequent co-deposition of Aβ, and hippocampal neurofibrillary tangles. (rostagno2005chromosome13dementias pages 4-6, garringer2010modelingfamilialbritish pages 3-4)
• Neuroimaging: ventricular dilatation and periventricular white-matter changes have been reported (nonspecific). (rostagno2005chromosome13dementias pages 4-6)

Table: This table summarizes currently supported diagnostic approaches, pathology findings, supportive care practices, and preclinical therapeutic leads for ADan amyloidosis/familial Danish dementia. It is useful for distinguishing established clinical implementation from experimental mechanisms-based interventions.

10.2 Differential diagnosis

Formal differential-diagnosis guidance was not retrieved. Based on pathology/phenotype overlap, differential considerations include other hereditary cerebral amyloid angiopathies, familial Alzheimer disease, and other inherited neurodegenerative syndromes with early cataracts/hearing loss/ataxia.

11. Outcome / prognosis

A multigenerational case series reported median age at death 58 years. No modern survival curves, prognostic models, or biomarker-based prognostic factors were retrieved. (rostagno2005chromosome13dementias pages 4-6)

12. Treatment

12.1 Current clinical management (real-world implementation)

No disease-modifying approved treatments were identified in the retrieved evidence. Current care is inferred to be supportive and multidisciplinary (vision, hearing, ataxia rehabilitation, cognitive/dementia care). (garringer2010modelingfamilialbritish pages 3-4, rostagno2005chromosome13dementias pages 4-6)

12.2 Experimental / preclinical therapeutic directions

• Anti-amyloid immunotherapy concept (preclinical): ADan-specific monoclonal antibody 1B7 completely neutralized ADan cytotoxicity in a neuronal cell model. (todd2016oxidativestressand pages 11-13, todd2016oxidativestressand pages 14-16)
• Anti-oxidant strategy (preclinical): Trolox reduced ADan-induced oxidative stress-linked caspase activation (figure-level evidence). (todd2016oxidativestressand pages 13-14, todd2016oxidativestressand media f315265f)
• Targeting APP metabolism (mechanistic modifier): human tissue and model data support altered APP processing in FDD and prevention of synaptic/memory phenotypes by APP haplodeficiency in models. (matsuda2011increasedaβppprocessing pages 4-5)
• Targeting microglial pathways: BRI2–TREM2 regulation and microglial phagocytosis effects suggest a possible therapeutic axis (early-stage hypothesis). (yin2024functionalbri2trem2interactions pages 1-2)

12.3 Clinical trials

A search of ClinicalTrials.gov within the current tool context retrieved no clearly relevant ADan/FDD interventional trials. (OpenTargets Search: familial Danish dementia,ADan amyloidosis-ITM2B)

13. Prevention

No primary-prevention strategies were retrieved. In practice, prevention is largely genetic counseling and cascade testing in affected families (concept supported by autosomal dominant inheritance and gene-defined diagnosis). (rostagno2005chromosome13dementias pages 4-6)

14. Other species / natural disease

No naturally occurring veterinary cases were retrieved in the current evidence set.

15. Model organisms

15.1 Mammalian models

• Transgenic FDD mice: age-dependent ADan deposition and cerebrovascular amyloid (CAA) and behavioral/motor abnormalities in some models, with onset of vascular pathology in early months in certain lines; crossing with tau P301S increases tau pathology. (garringer2010modelingfamilialbritish pages 4-6, garringer2010modelingfamilialbritish pages 6-7)
• Knock-in (KI) mice: some KI lines show synaptic/memory deficits with limited/no detectable amyloid deposition, underscoring mechanistic contributions beyond extracellular plaque burden and highlighting model limitations. (marcora2014amyloidpeptidesabri pages 1-2, garringer2010modelingfamilialbritish pages 6-7)
• Knock-in rats with humanized APP/Aβ: show vascular ADan deposition plus vascular Aβ, BBB leakage (fibrinogen extravasation), neuroinflammation, demyelination/axonal loss, and motor deficits—providing a platform for studying vascular/white-matter mechanisms. (choudhury2025pathologicalmechanismsof pages 1-2, choudhury2025pathologicalmechanismsof pages 15-16)

15.2 Invertebrate models

• Drosophila UAS models: ADan showed the highest age-dependent neurotoxicity among tested peptides, with functional motor decline detectable as early as 7 days post-eclosion in a geotaxis assay; deposits were thioflavin-S-negative, illustrating limitations in modeling fibrillar deposition. (marcora2014amyloidpeptidesabri pages 1-2)

15.3 In vitro / cellular models

• SH-SY5Y neuronal models show ADan-driven ROS and mitochondrial apoptosis, modifiable by Trolox and antibody neutralization. (todd2016oxidativestressand pages 11-13, todd2016oxidativestressand pages 13-14, todd2016oxidativestressand pages 14-16)
• iPSC-derived microglia studies (primarily FBD) show high ITM2B expression and peptide detection in microglial lysates/media, supporting microglial contributions to ITM2B-derived amyloid peptide biology. (arber2024microgliacontributeto pages 1-2)

Recent developments (prioritized 2023–2024)

1) Microglial production and enrichment of ITM2B/BRI2 (Acta Neuropathologica 2024): ITM2B expression is 34-fold higher in microglia vs neurons and 15-fold vs astrocytes, and patient iPSC-microglia contain detectable amyloidogenic peptide (ABri) in lysates and conditioned media; the same ITM2B processing logic applies to ADan generation in FDD. Publication date: Nov 2024; URL: https://doi.org/10.1007/s00401-024-02820-z (arber2024microgliacontributeto pages 1-2) 2) BRI2–TREM2 functional interaction (EMBO Reports 2024): demonstrates a direct BRI2–TREM2 ectodomain interaction, effects on TREM2 processing (TREM2-CTF/sTREM2), and reduced phagocytosis with Bri2 deletion. Publication date: Feb 2024; URL: https://doi.org/10.1038/s44319-024-00077-x (yin2024functionalbri2trem2interactions pages 1-2) 3) ADan sequence determinants and nucleation mapping (bioRxiv 2024): high-throughput mutagenesis maps an ADan amyloid core (L20–F26) and quantifies the distribution of nucleation-altering variants, providing a mechanistic framework for stop-loss amyloid diseases. Preprint posted 2024 (doi indicates 2023.09.15 submission); URL: https://doi.org/10.1101/2023.09.15.557952 (martin2024amyloids“atthe pages 3-5)

Key quantitative statistics (from retrieved studies)

• Natural history in a Danish pedigree series: 13 cases / 5 generations, median visual onset 27 years, median death 58 years. (rostagno2005chromosome13dementias pages 4-6)
• Human tissue (n=1 FDD vs n=1 control): soluble Aβ42 11×, insoluble Aβ42 125×, soluble Aβ40 27×, insoluble Aβ40 38×, sAPPβ 2.7×, sAPPα 5×. (matsuda2011increasedaβppprocessing pages 4-5)
• Cell-type expression (iPSC-derived): ITM2B/BRI2 expression 34× higher in microglia vs neurons and 15× higher vs astrocytes. (arber2024microgliacontributeto pages 1-2)

Evidence limitations and gaps

• Curated identifiers beyond MONDO (OMIM/Orphanet/MeSH/ICD) were not retrieved in the current context and should be filled by direct queries to those resources.
• Modern epidemiology (prevalence/incidence), penetrance estimates, and standardized diagnostic/treatment guidelines were not retrieved.
• Many therapeutic insights remain preclinical; no disease-specific interventional trial evidence was retrieved here.

Source list (URLs and dates available in retrieved texts)

• Rostagno et al., Cell Mol Life Sci (Jun 2005). https://doi.org/10.1007/s00018-005-5092-5 (rostagno2005chromosome13dementias pages 4-6)
• Garringer et al., Brain Struct Funct (Mar 2010). https://doi.org/10.1007/s00429-009-0221-9 (garringer2010modelingfamilialbritish pages 3-4)
• Matsuda et al., J Alzheimers Dis (Nov 2011). https://doi.org/10.3233/JAD-2011-110785 (matsuda2011increasedaβppprocessing pages 4-5)
• Todd et al., Neurobiol Dis (Jan 2016). https://doi.org/10.1016/j.nbd.2015.10.003 (todd2016oxidativestressand pages 11-13)
• Yin et al., EMBO Reports (Feb 2024). https://doi.org/10.1038/s44319-024-00077-x (yin2024functionalbri2trem2interactions pages 1-2)
• Arber et al., Acta Neuropathologica (Nov 2024). https://doi.org/10.1007/s00401-024-02820-z (arber2024microgliacontributeto pages 1-2)
• Martín & Bolognesi, bioRxiv (Aug 2024 posting/identifier). https://doi.org/10.1101/2023.09.15.557952 (martin2024amyloids“atthe pages 3-5)

References

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