Emergence of distinct and heterogeneous strains of amyloid beta with advanced Alzheimer’s disease pathology in Down syndrome
Year: 2021
Type: article
Study design: Observational Study
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.
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,170
Funders: National Science Foundation, University of Washington, Alzheimer's Society, Invitae, York University, Alzheimer Society, National Institute for Health and Care Research, King's College London, National Institutes of Health, University of California, San Diego, University of California, San Francisco, Medical Research Council, NIHR Oxford Biomedical Research Centre, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Alzheimer's Disease Research Center, Graduate Research Fellowship Program (GRFP), Pacific Udall Center, Alzheimer's Disease Patient Registry (ADPR/ACT), Degenerative and Dementing Diseases of Aging, Research Training in Chemistry and Chemical Biology, A 600 MHz NMR console and cryoprobe for studies of macromolecules, drug discovery and cancer biomarkers, G517332907, G5900765980, G7415375338, Alzheimer's Disease Research Center, Relationships between conformational strains of tau and amyloid-beta, TREM2 and APOE variants, and phenotypic variations of Alzheimer's Disease, University of Washington Alzheimer's Disease Research Center, The Alzheimer's Disease Research Center at the University of California, Irvine
OpenAlex ID: W4200501434