MODELS OF AMYLOID SEEDING IN ALZHEIMER'S DISEASE AND SCRAPIE: Mechanistic Truths and Physiological Consequences of the Time-Dependent Solubility of Amyloid Proteins
Abstract
Ordered protein aggregation in the brain is a hallmark of Alzheimer's disease and scrapie. The disease-specific amyloid fibrils comprise primarily a single protein, amyloid beta, in Alzheimer's disease, and the prion protein in scrapie. These proteins can be induced to form aggregates in vitro that are indistinguishable from brain-derived fibrils. Consequently, much effort has been invested in the development of in vitro model systems to study the details of the aggregation processes and the effects of endogenous molecules that have been implicated in disease. Selected studies of this type are reviewed herein. A simple mechanistic model has emerged for both processes that involves a nucleation-dependent polymerization. This mechanism dictates that aggregation is dependent on protein concentration and time. Furthermore, amyloid formation can be seeded by a preformed fibril. The physiological consequences of this mechanism are discussed.
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Ongoing microglial phagocytosis around growing fibrillar deposits could reduce levels of oligomeric and protofibrillar Aβ, which may change the equilibrium between monomers, oligomers and fibrils, altering nucleation-dependent polymerization that leads to fibrillar plaque formation.
“Ongoing microglial phagocytosis around growing fibrillar deposits could reduce levels of oligomeric and protofibrillar Aβ, which may change the equilibrium between monomers, oligomers and fibrils, altering the process of nucleation-dependent polymerization that leads to fibrillar plaque formation (Harper and Lansbury Jr., 1997; Walsh et al., 1999).”
From CX3CR1 in Microglia Regulates Brain Amyloid Deposition through Selective Protofibrillar Amyloid-β Phagocytosis (2010) · cites this paper as Harper and Lansbury Jr., 1997
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- Authors
- Harper, J. D., & Lansbury, P. T.
- Affiliations
- Massachusetts Institute of Technology (US)
- Brigham and Women's Hospital (US)
- Venue
- Annual Review of Biochemistry
- Publisher
- Annual Reviews
- Published
- 1997-06
- Volume
- 66
- Issue
- 1
- Pages
- 385-407
- ISSN
- 0066-4154 (ISSN-L)
- 1545-4509
- OpenAlex
- W2096601751
- Cited by
- 1,652
- References
- 10
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 33 · 2023: 22 · 2022: 23 · 2021: 45 · 2020: 39 · 2019: 45 · 2018: 50 · 2017: 55 · 2016: 56 · 2015: 66 · 2014: 67 · 2013: 110 · 2012: 81
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid seeding, Alzheimer's disease, scrapie, amyloid-beta, prion protein, protein aggregation, amyloid fibrils, prion propagation
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Amyloid, Animals, Brain, Humans, Molecular Sequence Data, Scrapie, Solubility, Time Factors
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