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Cited by 487Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology

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Lemere, Cynthia A., Lopera, Francisco, Kosik, Kenneth S., Lendon, Corrine L., Ossa, Jorge, Saido, Takaomi C., Yamaguchi, Haruyasu, Ruiz, Andres +9 more·1996·Nature Medicine
DOI 10.1038/nm1096-1146
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Abstract

Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early-onset familial Alzheimer's disease (FAD) and are associated with increased levels of amyloid beta-peptides (A beta) ending at residue 42 (A beta 42) in plasma and skin fibroblast media of gene carriers. A beta 42 aggregates readily and appears to provide a nidus for the subsequent aggregation of A beta 40 (ref. 4), resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1-FAD patients from a large Colombian kindred bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation. Using antibodies specific to the alternative carboxy-termini of A beta, we detected massive deposition of A beta 42, the earliest and predominant form of plaque A beta to occur in AD (ref. 6-8), in many brain regions. Computer-assisted quantification revealed a significant increase in A beta 42, but not A beta 40, burden in the brains from 4 PS1-FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous A beta 42-reactive plaques, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased A beta 42 levels in PS1-FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the beta-amyl…

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Crossref · 10.1038/nm1096-1146

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  • Human PSEN1 mutation carriers have notable BBB breakdown and cerebrovascular dysfunction including cerebellar amyloid angiopathy and CAA, disrupted meningeal, subpial, and cortical arterioles, degeneration of pericytes and SMCs, cerebral perivascular amyloid deposits, and diminished FDG transport across the BBB in an early asymptomatic stage.

    “Human PSEN1 mutation carriers have notable BBB breakdown and cerebrovascular dysfunction including cerebellar amyloid angiopathy and CAA (143, 183, 274, 280, 354, 389, 440, 500, 544, 573, 639, 668); disrupted meningeal, subpial, and cortical arterioles (274, 389, 440); degeneration of pericytes and SMCs (573); cerebral perivascular amyloid deposits (25, 274, 289, 354, 573, 668); and diminished FDG”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [354]

  • The reported patient was protected from clinical effects of PSEN1-E280A, a highly penetrant EOAD mutation, for 28 years by the homozygous APOE3-R136S mutation.

    “The reported patient was protected from the clinical effects of PSEN1-E280A, a highly penetrant mutation causing EOAD dementia41,42, for 28 years by the homozygous APOE3-R136S mutation36.”

    From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [42]

  • PSEN1 E280A mutant neurons produce more Aβ42 than WT neurons.

    “Because PSEN1 E280A mutant neurons produce more Aβ42 than WT neurons,54 the elevated expression of ACSL1 in APOE3 microglia co-cultured with PSEN1 mutant but not WT neurons prompted us to investigate the role of Aβ42 in the induction of ACSL1 expression.”

    From Microglial APOE3 Christchurch protects neurons from Tau pathology in a human iPSC-based model of Alzheimer’s disease (2024) · cites this paper as [54]

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Authors
Lemere, C. A., Lopera, F., Kosik, K. S., Lendon, C. L., Ossa, J., Saido, T. C., Yamaguchi, H., Ruiz, A., Martinez, A., Madrigal, L., Hincapie, L., Arango L., J. C., Anthony, D. C., Koo, E. H., Goate, A. M., Selkoe, D. J., & Arango V., J. C.
Affiliations
  • Brigham and Women's Hospital (US)
  • Universidad de Antioquia (CO)
  • Washington University in St. Louis (US)
  • Tokyo Metropolitan Institute of Medical Science (JP)
  • Gunma University (JP)
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
1996-10
Volume
2
Issue
10
Pages
1146-1150
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm1096-1146
OpenAlex
W2086523105
Cited by
487
References
4
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 10 · 2022: 4 · 2021: 20 · 2020: 18 · 2019: 9 · 2018: 10 · 2017: 9 · 2016: 11 · 2015: 11 · 2014: 15 · 2013: 10 · 2012: 16
FWCI
27.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Repository University of Antioquia (University of Antioquia) (publishedVersion, cc-by)
Funders
National Institute on Aging (AG-06173, AG-00634)
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
presenilin 1, familial Alzheimer's disease, amyloid-beta 42, amyloid deposition, cerebellar pathology, neuritic plaques, dystrophic neurites, reactive glia, sporadic Alzheimer's disease
MeSH terms
Aged, Alzheimer Disease, Brain Chemistry, Cerebellum, Codon, Female, Humans, Image Processing, Computer-Assisted, Male, Membrane Proteins, Middle Aged, Nerve Tissue Proteins, Amyloid beta-Peptides, Neurofibrillary Tangles, Point Mutation, Age of Onset, Presenilin-1

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