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Emergence of distinct and heterogeneous strains of amyloid beta with advanced Alzheimer's disease pathology in Down syndrome.

ABSTRACT: Amyloid beta (Aβ) is thought to play a critical role in the pathogenesis of Alzheimer's disease (AD). Prion-like Aβ polymorphs, or "strains", can have varying pathogenicity and may underlie the phenotypic heterogeneity of the disease. In order to develop effective AD therapies, it is critical to identify the strains of Aβ that might arise prior to the onset of clinical symptoms and understand how they may change with progressing disease. Down syndrome (DS), as the most common genetic cause of AD, presents promising opportunities to compare such features between early and advanced AD. In this work, we evaluate the neuropathology and Aβ strain profile in the post-mortem brain tissues of 210 DS, AD, and control individuals. We assayed the levels of various Aβ and tau species and used conformation-sensitive fluorescent probes to detect differences in Aβ strains among individuals and populations. We found that these cohorts have some common but also some distinct strains from one another, with the most heterogeneous populations of Aβ emerging in subjects with high levels of AD pathology. The emergence of distinct strains in DS at these later stages of disease suggests that the confluence of aging, pathology, and other DS-linked factors may favor conditions that generate strains that are unique from sporadic AD.

SUBMITTER: Maxwell AM

PROVIDER: S-EPMC8711167 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Emergence of distinct and heterogeneous strains of amyloid beta with advanced Alzheimer's disease pathology in Down syndrome.

Maxwell Alison M AM Yuan Peng P Rivera Brianna M BM Schaaf Wilder W Mladinov Mihovil M Prasher Vee P VP Robinson Andrew C AC DeGrado William F WF Condello Carlo C

Acta neuropathologica communications 20211227 1

Amyloid beta (Aβ) is thought to play a critical role in the pathogenesis of Alzheimer's disease (AD). Prion-like Aβ polymorphs, or "strains", can have varying pathogenicity and may underlie the phenotypic heterogeneity of the disease. In order to develop effective AD therapies, it is critical to identify the strains of Aβ that might arise prior to the onset of clinical symptoms and understand how they may change with progressing disease. Down syndrome (DS), as the most common genetic cause of AD ...[more]

PMID: 34961556

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Project description:Down syndrome (DS, trisomy 21) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21) encoding the Alzheimer's disease (AD) amyloid precursor protein (APP). Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-beta peptides (Abeta), early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased Abeta accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked Abeta pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear Abeta accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Abeta aggregates (approximately 5 to 50 nm) identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of Abeta in DS lenses. Incubation of synthetic Abeta with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased Abeta accumulation as a key pathogenic determinant linking lens and brain pathology in both DS and AD.

Project description: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 the lenses of people with AD. Subsequent research identified Aβ lens pathology as the molecular origin of the distinctive cataracts associated with 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 a decade or more 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 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.

Dataset Information

Emergence of distinct and heterogeneous strains of amyloid beta with advanced Alzheimer's disease pathology in Down syndrome.

Publications

Emergence of distinct and heterogeneous strains of amyloid beta with advanced Alzheimer's disease pathology in Down syndrome.

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