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Cited by 342Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice

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Harris, Faith M., Brecht, Walter J., Xu, Qin, Tesseur, Ina, Kekonius, Lisa, Wyss-Coray, Tony, Fish, Jo Dee, Masliah, Eliezer +6 more·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1434398100PMC PMC196910
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Abstract

Apolipoprotein (apo) E4 increases the risk and accelerates the onset of Alzheimer's disease (AD). However, the underlying mechanisms remain to be determined. We previously found that apoE undergoes proteolytic cleavage in AD brains and in cultured neuronal cells, resulting in the accumulation of carboxyl-terminal-truncated fragments of apoE that are neurotoxic. Here we show that this fragmentation is caused by proteolysis of apoE by a chymotrypsin-like serine protease that cleaves apoE4 more efficiently than apoE3. Transgenic mice expressing the carboxyl-terminal-cleaved product, apoE4(Δ272–299), at high levels in the brain died at 2–4 months of age. The cortex and hippocampus of these mice displayed AD-like neurodegenerative alterations, including abnormally phosphorylated tau (p-tau) and Gallyas silver-positive neurons that contained cytosolic straight filaments with diameters of 15–20 nm, resembling preneurofibrillary tangles. Transgenic mice expressing lower levels of the truncated apoE4 survived longer but showed impaired learning and memory at 6–7 months of age. Thus, carboxyl-terminal-truncated fragments of apoE4, which occur in AD brains, are sufficient to elicit AD-like neurodegeneration and behavioral deficits in vivo . Inhibiting their formation might inhibit apoE4-associated neuronal deficits.

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Authors
Harris, F. M., Brecht, W. J., Xu, Q., Tesseur, I., Kekonius, L., Wyss-Coray, T., Fish, J. D., Masliah, E., Hopkins, P. C., Scearce-Levie, K., Weisgraber, K. H., Mucke, L., Mahley, R. W., & Huang, Y.
Affiliations
  • University of California, San Francisco (US)
  • Gladstone Institute of Neurological Disease and Gladstone Institute of Cardiovascular Disease, P.O. Box 419100, San Francisco, CA 94141-9100; Departments of Neurology, Pathology, and Medicine, University of California, San Francisco, CA 94143; and Departments of Neurosciences and Pathology, University of California at San Diego, La Jolla, CA 92093
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2003-08-25
Volume
100
Issue
19
Pages
10966-10971
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1434398100
PMC
PMC196910
OpenAlex
W2171960085
Cited by
342
References
60
Citations by year
2026: 7 · 2025: 9 · 2024: 10 · 2023: 10 · 2022: 14 · 2021: 16 · 2020: 11 · 2019: 18 · 2018: 11 · 2017: 16 · 2016: 27 · 2015: 9 · 2014: 21 · 2013: 18 · 2012: 21
FWCI
9.99
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion)
Funders
National Institute on Aging (P01AG022074)
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
APOE ε4, carboxyl-terminal truncation, proteolytic cleavage, chymotrypsin-like serine protease, neurodegeneration, Alzheimer's disease, tau phosphorylation, neurofibrillary tangles, learning and memory impairment, transgenic mice, neurotoxicity
MeSH terms
Aged, Animals, Apolipoproteins E, Behavior, Animal, Brain, Humans, Hydrolysis, Mice, Transgenic, Microscopy, Electron, Mice, Apolipoprotein E4

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