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Amyloid Associated with Neurodegenerative Diseases

Published on: 16 Jun 2022 Viewed: 203

Our staff editors continue to share brilliant, thoughtful, and meaningful topics and articles in the recommended series.

This week, we would like to share newest articles on amyloid associated with neurodegenerative diseases.

Title: Amyloid β, Tau, and α-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases
Authors: Urmi Sengupta, Rakez Kayed
Type: Review Article
●Co-occurring proteinopathies confound disease diagnosis and treatment development.
●Overlapping Aβ, tau, and α-Syn pathologies are observed in AD and related diseases.
●Aβ, tau, and α-Syn converge directly or indirectly in in vitro and in vivo.
●We review recent advancements in biomarkers and neuroimaging for Aβ, tau, and α-Syn.
●A combined therapeutic approach might be more successful for disease intervention.
Aggregation of specific proteins are histopathological hallmarks of several neurodegenerative diseases, such as, Amyloid β (Aβ) plaques and tau neurofibrillary tangles in Alzheimer’s disease (AD); morphologically different inclusions of ratiometric 3 repeat (3 R) and 4 repeat (4 R) tau isoforms in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD); α-Synuclein (α-Syn) containing Lewy bodies (LBs) and dystrophic Lewy neurites (LNs) in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, mixed brain protein pathologies have been frequently observed in many of these diseases and in normal aging brains, among which Aβ/tau and tau/α-Syn crosstalks have received increased attention. Interestingly, studies have also shown synergistic interplay among Aβ, tau, and α-Syn in several neurodegenerative diseases, suggesting a protein triumvirate. In this review, we summarize the emerging evidence of Aβ, tau, and α-Syn aggregation in pathophysiology, and their overlap in a spectrum of neurodegenerative diseases including AD, PSP, PiD, CBD, PD and DLB. We discuss the prognostic advancements made in biomarker and imaging techniques in the triumvirate proteinopathies. Finally, we discuss the combined therapeutic modality involving biomarkers and imaging techniques for future combinatorial immunotherapeutic targeting more than one protein aggregates. We hope that such a multitarget therapeutic approach will have synergistic or additive effects to manage neurodegenerative diseases with two or more protein pathologies that might uncover a promising strategy for personalized combination therapies. Managing neurodegenerative diseases by optimizing the diagnostic criteria and the correct combination of immunotherapies will be a key factor in the success of future treatment.
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Title: Amyloid, cerebrovascular disease, and neurodegeneration biomarkers are associated with cognitive trajectories in a racially and ethnically diverse, community-based sample
Authors: Patrick J. Lao, Amelia K. Boehme, Clarissa Morales, Krystal K. Laing, Anthony Chesebro, Kay C. Igwe, Jose Gutierrez, Yian Gu, Yaakov Stern, Nicole Schupf, Jennifer J. Manly, Richard Mayeux, Adam M. Brickman
Type: Research Article
●Greater amyloid was associated with faster memory decline in older adults.
●Greater amyloid was associated with faster non–memory decline in older Non-Hispanic Black and Hispanic adults.
●White matter hyperintensity (WMH) was greater in older Non-Hispanic adults and associated with faster multidomain cognitive decline.
●Infarcts were associated with faster executive function decline in older Non-Hispanic white adults.
●Amyloid-vascular-neurodegeneration (AV(N)) models are relevant for Alzheimer's disease in all groups, particularly when considering social determinants of health.
We characterized the additive contribution of cerebrovascular biomarkers to amyloid and neurodegeneration biomarkers (AV(N)) when modeling prospective, longitudinal cognitive trajectories within 3 major racial/ethnic groups. Participants (n = 172; age = 69–96 years; 62% women; 31%/49%/20% Non–Hispanic White/Non–Hispanic Black/Hispanic) from the Washington Heights-Inwood Columbia Aging Project were assessed for amyloid (Florbetaben PET), neurodegeneration (cortical thickness, hippocampal volume), and cerebrovascular disease (white matter hyperintensity (WMH), infarcts). Neuropsychological assessments occurred every 2.3 ± 0.6 years for up to 6 visits (follow-up time: 4.2 ± 3.2 years). Linear mixed-effects models were stratified by race/ethnicity groups. Higher amyloid was associated with faster memory decline in all 3 racial/ethnic groups, but was related to faster cognitive decline beyond memory in minoritized racial/ethnic groups. Higher WMH was associated with faster language, processing speed/executive function, and visuospatial ability decline in Non–Hispanic Black participants, while infarcts were associated with faster processing speed/executive function decline in Non–Hispanic White participants. Complementary information from AD, neurodegenerative, and cerebrovascular biomarkers explain decline in multiple cognitive domains, which may differ within each racial/ethnic group. Importantly, treatment strategies exist to minimize vascular contributions to cognitive decline.
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Title: Phloroglucinol, a clinical-used antispasmodic, inhibits amyloid aggregation and degrades the pre-formed amyloid proteins
Authors: Yanfei Xie, Jiani Lu, Tiantian Yang, Chao Chen, Yongjie Bao, Luying Jiang, Hua Wei, Xiang Wu, Li Zhao, Shan He, Dongdong Lin, Fufeng Liu, Hao Liu, Xiaojun Yan, Wei Cui
Type: Research Article
Amyloid proteins, such as β-amyloid (Aβ) and α-synuclein (α-syn), could form neurotoxic aggregates during the progression of neurodegenerative disorders. Phloroglucinol, a clinical-used drug for treating spasmodic pain, was predicted to cross the blood brain-barrier and possesses neuroprotective potential. In this study, we have found, for the first time, that phloroglucinol inhibited the formation of amyloid aggregates, and degraded pre-formed amyloid aggregates with the similar efficacy as curcumin, a widely known amyloid aggregation inhibitor. Moreover, phloroglucinol decreased the seeding during aggregation process and inhibited the aggregation of Aβ1–42 with homocysteine (Hcy) seeds. Molecular docking analysis further demonstrated hydrophobic interactions and hydrogen bonds between phloroglucinol and Aβ1–42/α-syn. Furthermore, phloroglucinol inhibited amyloid aggregates-induced cytotoxicity in neuronal cells and prevented Aβ1–42 + Hcy aggregates-induced cognitive impairments in mice. All these results suggested that phloroglucinol possesses the ability to degrade pre-formed amyloid aggregates, to inhibit the seeding during amyloid aggregation, and to reduce the neurotoxicity, indicating the reposition possibility of phloroglucinol as a novel drug for treating neurodegenerative disorders.
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Title: Functional Imaging for Neurodegenerative Diseases
Authors: François CHOLLET, Pierre PAYOUX
Type: Mini Review
Diagnosis and monitoring of neurodegenerative diseases has changed profoundly over the past twenty years. Biomarkers are now included in most diagnostic procedures as well as in clinical trials. Neuroimaging biomarkers provide access to brain structure and function over the course of neurodegenerative diseases. They have brought new insights into a wide range of neurodegenerative diseases and have made it possible to describe some of the imaging challenges in clinical populations. MRI mainly explores brain structure while molecular imaging, functional MRI and electro- and magnetoencephalography examine brain function. In this paper, we describe and analyse the current and potential contribution of MRI and molecular imaging in the field of neurodegenerative diseases.
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Title: Alzheimer's disease amyloid-β pathology in the lens of the eye
Authors: Juliet A. Moncaster, Robert D. Moir, Mark A. Burton, Oliver Chadwick, Olga Minaeva, Victor E. Alvarez, Maria Ericsson, John I. Clark, Ann C. McKee, Rudolph E. Tanzi, Lee E. Goldstein
Type: Research Article
●We review Aβ lens pathology in Alzheimer's disease (AD) and Down syndrome (DS).
●Light-scattering Aβ microaggregates lead to AD-related supranuclear cataract (SNC).
●We report human Aβ lens pathology and SNC in Tg2576 transgenic mouse model of AD.
●Our results provide the first evidence of AD-related Aβ pathology outside the brain.
●Lens Aβ can be noninvasively measured in vivo for early AD detection and monitoring.
Neuropathological hallmarks of Alzheimer's disease (AD) include pathogenic accumulation of amyloid-β (Aβ) peptides and age-dependent formation of amyloid plaques in the brain. AD-associated Aβ neuropathology begins decades before onset of cognitive symptoms and slowly progresses over the course of the disease. We previously reported discovery of Aβ deposition, β-amyloidopathy, and co-localizing supranuclear cataracts (SNC) in lenses from people with AD, but not other neurodegenerative disorders or normal aging. We confirmed AD-associated Aβ molecular pathology in the lens by immunohistopathology, amyloid histochemistry, immunoblot analysis, epitope mapping, immunogold electron microscopy, quantitative immunoassays, and tryptic digest mass spectrometry peptide sequencing. Ultrastructural analysis revealed that AD-associated Aβ deposits in AD lenses localize as electron-dense microaggregates in the cytoplasm of supranuclear (deep cortex) fiber cells. These Aβ microaggregates also contain αB-crystallin and scatter light, thus linking Aβ pathology and SNC phenotype expression in AD lenses. Subsequent research identified Aβ lens pathology as the molecular origin of the distinctive cataracts in Down syndrome (DS, trisomy 21), a chromosomal disorder invariantly associated with early-onset Aβ accumulation and Aβ amyloidopathy in the brain. Investigation of 1249 participants in the Framingham Eye Study found that AD-associated quantitative traits in brain and lens are co-heritable. Moreover, AD-associated lens traits preceded MRI brain traits and cognitive deficits by ∼10 years and predicted future AD. A genome-wide association study of bivariate outcomes in the same subjects identified a new AD risk factor locus in the CTNND2 gene encoding δ-catenin, a protein that modulates Aβ production in brain and lens. Here we report identification of AD-related human Aβ (hAβ) lens pathology and age-dependent SNC phenotype expression in the Tg2576 transgenic mouse model of AD. Tg2576 mice express Swedish mutant human amyloid precursor protein (APP-Swe), accumulate hAβ peptides and amyloid pathology in the brain, and exhibit cognitive deficits that slowly progress with increasing age. We found that Tg2576 trangenic (Tg+) mice, but not non-transgenic (Tg–) control mice, also express human APP, accumulate hAβ peptides, and develop hAβ molecular and ultrastructural pathologies in the lens. Tg2576 Tg+ mice also exhibit age-dependent Aβ supranuclear lens opacification that recapitulates lens pathology and SNC phenotype expression in human AD. In addition, we detected hAβ in conditioned medium from lens explant cultures prepared from Tg+ mice, but not Tg– control mice, a finding consistent with constitutive hAβ generation in the lens. In vitro studies showed that hAβ promoted mouse lens protein aggregation detected by quasi-elastic light scattering (QLS) spectroscopy. These results support mechanistic (genotype-phenotype) linkage between Aβ pathology and AD-related phenotypes in lens and brain. Collectively, our findings identify Aβ pathology as the shared molecular etiology of two age-dependent AD-related cataracts associated with two human diseases (AD, DS) and homologous murine cataracts in the Tg2576 transgenic mouse model of AD. These results represent the first evidence of AD-related Aβ pathology outside the brain and point to lens Aβ as an optically-accessible AD biomarker for early detection and longitudinal monitoring of this devastating neurodegenerative disease.
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