Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models
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Alzheimer disease (AD) is characterized by amyloid-β accumulation, with soluble oligomers (Aβo) being the most synaptotoxic. However, the multivalent and unstable nature of Aβo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aβo forms throughout the life span of various AD mice and in post-mortem human brain. Aβo exists in several populations, where prion protein (PrP(C))-interacting Aβo is a high molecular weight Aβ assembly present in multiple mice and humans with AD. Levels of PrP(C)-interacting Aβo match closely with mouse memory and are equal or superior to other Aβ measures in predicting behavioral impairment. However, Aβo metrics vary considerably between mouse strains. Deleting PrP(C) expression in mice with relatively low PrP(C)-interacting Aβo (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrP(C)-interacting Aβo (APP/PSEN1). These findings highlight the relative contributions and interplay of Aβo forms in AD.
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oAβ, especially high-molecular weight oligomers, preferentially bind to PrPC within an N-terminal 95-111aa segment.
“Subsequent studies showed that oAβ, especially high-molecular weight oligomers [88], preferentially bind to PrPC within an N-terminal 95-111aa segment [87].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [88]
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References 90 · Cited by 133
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- JOURNAL OF BIOLOGICAL CHEMISTRY 17435
- Authors
- Kostylev, M. A., Kaufman, A. C., Nygaard, H. B., Patel, P., Haas, L. T., Gunther, E. C., Vortmeyer, A., & Strittmatter, S. M.
- Affiliations
- Yale University (US)
- Corresponding author
- Strittmatter, Stephen M.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 290
- Issue
- 28
- Pages
- 17415-17438
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4498078
- OpenAlex
- W1606575263
- Cited by
- 133
- References
- 90
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 16 · 2022: 13 · 2021: 11 · 2020: 6 · 2019: 15 · 2018: 17 · 2017: 19 · 2016: 15 · 2015: 3
- FWCI
- 13.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- BrightFocus Foundation
- Dr. Ralph and Marian Falk Medical Research Trust
- National Institutes of Health
- National Institute on Aging (P50AG047270, R01AG034924)
- National Institute of General Medical Sciences (T32GM007205)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta oligomers, prion protein, memory impairment, cognitive impairment, Tg2576 mice, synaptotoxicity, postmortem brain
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Behavior, Animal, Disease Models, Animal, Female, Humans, Male, Memory Disorders, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Middle Aged, Molecular Weight, Prions, Recombinant Proteins, Amyloid beta-Peptides, Prefrontal Cortex, PrPC Proteins, Protein Structure, Quaternary, Mice, Presenilin-1
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