The carboxy terminus of the .beta. amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease

Jarrett, Joseph T.; Berger, Elizabeth P.; Lansbury, Peter T.

doi:10.1021/bi00069a001

Cited by 2,022Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchPrion Diseases and Protein Misfolding

The carboxy terminus of the .beta. amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease

Jarrett, Joseph T., Berger, Elizabeth P., Lansbury, Peter T.·1993·Biochemistry

DOI 10.1021/bi00069a001

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Abstract

Several variants of the beta amyloid protein, differing only at their carboxy terminus (beta 1-39, beta 1-40, beta 1-42, and beta 1-43), have been identified as the major components of the cerebral amyloid deposits which are characteristic of Alzheimer's disease. Kinetic studies of aggregation by three naturally occurring beta protein variants (beta 1-39, beta 1-40, beta 1-42) and four model peptides (beta 26-39, beta 26-40, beta 26-42, beta 26-43) demonstrate that amyloid formation, like crystallization, is a nucleation-dependent phenomenon. This discovery has practical consequences for studies of the beta amyloid protein. The length of the C-terminus is a critical determinant of the rate of amyloid formation ("kinetic solubility") but has only a minor effect on the thermodynamic solubility. Amyloid formation by the kinetically soluble peptides (e.g., beta 1-39, beta 1-40, beta 26-39, beta 26-40) can be nucleated, or "seeded", by peptides which include the critical C-terminal residues (beta 1-42, beta 26-42, beta 26-43, beta 34-42). These results suggest that nucleation may be the rate-determining step of in vivo amyloidogenesis and that beta 1-42 and/or beta 1-43, rather than beta 1-40, may be the pathogenic protein(s) in AD.

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Synthetic Aβ1-42 forms amyloid fibrils in vitro much more readily than Aβ1-40.
“Synthetic A␤1-42 forms amyloid fibrils in vitro much more readily than A␤1-40 (Jarrett et al., 1993)”
From Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease (2001) · cites this paper as Jarrett et al., 1993

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Authors: Jarrett, J. T., Berger, E. P., & Lansbury, P. T.
Affiliations: Massachusetts Institute of Technology (US)
ORCID: Jarrett, Joseph T.
Lansbury, Peter T.
Venue: Biochemistry
Publisher: American Chemical Society (ACS)
Published: 1993-05-11
Volume: 32
Issue: 18
Pages: 4693-4697
ISSN: 0006-2960 (ISSN-L)
1520-4995
DOI: 10.1021/bi00069a001
OpenAlex: W2071953900
Cited by: 2,022
References: 3
Citations by year: 2026: 33 · 2025: 47 · 2024: 45 · 2023: 36 · 2022: 52 · 2021: 73 · 2020: 70 · 2019: 58 · 2018: 61 · 2017: 68 · 2016: 79 · 2015: 71 · 2014: 93 · 2013: 82 · 2012: 99
FWCI: 30.22
Type: journal article
Language: en
Open access: closed
Locations: Biochemistry (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5t32gm008318-04)
National Institute on Aging (AG08470-01, R01AG008470)
National Institute of General Medical Sciences (1T32GM08318-01)
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Keywords: beta-amyloid protein, C-terminal truncation, amyloid seeding, nucleation, Alzheimer's disease pathogenesis, amyloid fibril formation, kinetic solubility, thermodynamic solubility
MeSH terms: Alzheimer Disease, Amino Acid Sequence, Amyloid, Humans, Models, Biological, Molecular Sequence Data, Peptide Fragments, Protein Conformation, Solubility, Spectrophotometry, Infrared, Thermodynamics, Time Factors, Amyloid beta-Peptides

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The carboxy terminus of the .beta. amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease

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