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Cited by 133Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

The DOI matches its Crossref record; 82 of the 83 references it cites were found in a registry or an index.

Presenilin-1 P264L Knock-In Mutation: Differential Effects on Aβ Production, Amyloid Deposition, and Neuronal Vulnerability

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Siman, Robert, Reaume, Andrew G., Savage, Mary J., Trusko, Stephen, Lin, Yin-Guo, Scott, Richard W., Flood, Dorothy G.·2000·The Journal of Neuroscience
DOI 10.1523/jneurosci.20-23-08717.2000PMC PMC6773081
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Abstract

The pathogenic mechanism linking presenilin-1 (PS-1) gene mutations to familial Alzheimer's disease (FAD) is uncertain, but has been proposed to include increased neuronal sensitivity to degeneration and enhanced amyloidogenic processing of the β-amyloid precursor protein (APP). We investigated this issue by using gene targeting with the Cre-lox system to introduce an FAD-linked P264L mutation into the endogenous mouse PS-1 gene, an approach that maintains normal regulatory controls over expression. Primary cortical neurons derived from PS-1 homozygous mutant knock-in mice exhibit basal neurodegeneration similar to their PS-1 wild-type counterparts. Staurosporine and Aβ1–42 induce apoptosis, and neither the dose dependence nor maximal extent of cell death is altered by the PS-1 knock-in mutation. Similarly, glutamate-induced neuronal necrosis is unaffected by the PS-1P264L mutation. The lack of effect of the PS-1P264L mutation is confirmed by measures of basal- and toxin-induced caspase and calpain activation, biochemical indices of apoptotic and necrotic signaling, respectively. To analyze the influence of the PS-1P264L knock-in mutation on APP processing and the development of AD-type neuropathology, we created mouse lines carrying mutations in both PS-1 and APP. In contrast to the lack of effect on neuronal vulnerability, cortical neurons cultured from PS-1P264L homozygous mutant mice secrete Aβ42 at an increased rate, whereas secretion of Aβ40 is reduced. Moreover, the PS-1 knock-in mutation selectively increases Aβ42 levels in the mouse brain and accelerates the onset of amyloid deposition and its attendant reactive gliosis, even as a single mutant allele. We conclude that expression of an FAD-linked mutant PS-1 at normal levels does not generally increase cortical neuronal sensitivity to degeneration. Instead, enhanced amyloidogenic processing of APP likely is critical to the pathogenesis of PS-1-linked FAD.

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Research works printed but not linked: 2

  1. Dorfman, 1998, Creation and characterization of two distinct types of mutations in PS-1 using gene targeting in mice., Soc Neurosci Abstr, 24, 472
  2. Siman R Durkin JT Husten EJ Savage MJ Murthy S Mistretta S Chatterjee S Rotella DP Dembofsky B Poorman R Greenberg BD (1995) Genesis and degradation of Aβ protein by cultured human neuroblastoma cells. in Research advances in Alzheimer's disease and related disorders, eds Iqbal K Mortimer J Winblad B Wisniewski H (Wiley, Sussex, UK), pp 675–684.

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Metadata

Authors
Siman, R., Reaume, A. G., Savage, M. J., Trusko, S., Lin, Y.-G., Scott, R. W., & Flood, D. G.
Affiliations
University of Pennsylvania (US)
ORCID
Reaume, Andrew G.
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2000-12-01
Volume
20
Issue
23
Pages
8717-8726
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.20-23-08717.2000
PMC
PMC6773081
OpenAlex
W1651448739
Cited by
133
References
83
Citations by year
2026: 2 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 2 · 2013: 10 · 2012: 4
FWCI
3.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
presenilin 1, familial Alzheimer's disease, amyloid-beta production, amyloid-beta 42, amyloid deposition, neuronal vulnerability, cortical neurons, apoptosis, staurosporine, caspase activation, calpain, APP processing, reactive gliosis
MeSH terms
Alzheimer Disease, Amyloid, Animals, Calpain, Cell Survival, Cells, Cultured, Cerebral Cortex, Disease Models, Animal, Homozygote, Membrane Proteins, Mice, Mutant Strains, Mice, Transgenic, Neurons, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Apoptosis, Gene Targeting, Glutamic Acid, Staurosporine, Amino Acid Substitution, Caspases, Mice, Presenilin-1

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