C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-β (Aβ) and acts in concert with Aβ to elicit neuronal and behavioral deficits in mice
Open accessAbstract
Apolipoprotein (apo) E4 is the major known genetic risk factor for Alzheimer's disease (AD). We have shown in vitro and in vivo that apoE4 preferentially undergoes aberrant cleavage in neurons, yielding neurotoxic C-terminal-truncated fragments. To study the effect of these fragments on amyloid-β (Aβ) clearance/deposition and their potential synergy with Aβ in eliciting neuronal and behavioral deficits, we cross-bred transgenic mice expressing apoE3, apoE4, or apoE4(Δ272–299) with mice expressing human amyloid protein precursor (APP) harboring familial AD mutations (hAPP FAD ). At 6–8 mo of age, hAPP FAD mice expressing apoE3 or apoE4 had lower levels of hippocampal Aβ (94% and 89%, respectively) and less Aβ deposition (89% and 87%) than hAPP FAD mice without apoE, whereas hAPP FAD mice expressing mouse apoE had higher Aβ levels. Thus, human apoE stimulates Aβ clearance, but mouse apoE does not. Expression of apoE4(Δ272–299) reduced total Aβ levels by only 63% and Aβ deposition by 46% compared with hAPP FAD mice without apoE. Unlike apoE3 and apoE4, the C-terminal-truncated apoE4 bound poorly with Aβ peptides, leading to decreased Aβ clearance and increased Aβ deposition. Despite their lower levels of Aβ and Aβ deposition, hAPP FAD /apoE4(Δ272–299) mice accumulated pathogenic Aβ oligomers and displayed neuronal and behavioral deficits similar to or more severe than those in hAPP FAD mice. Thus, the C-terminal-truncated apoE4 fragment inefficiently clears Aβ peptides and acts in concert with low levels of Aβ to elicit neuronal and behavioral deficits in mice.
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APOE exerts toxic effects on the cerebrovascular system and neurons and influences Aβ clearance, amyloid deposition, and tau-related neurodegeneration in an allele-dependent manner APOE4 > APOE3 > APOE2.
“APOE exerts toxic effects on the cerebrovascular system (694) and neurons (383, 384) and influences A 𝛃 clearance (60, 64, 98, 135, 256, 266, 278, 294, 315, 693), amyloid deposition (39, 256, 258, 266, 278, 314, 518, 612), and tau-related neurodegeneration (533) in an allele-dependent manner APOE4 > APOE3 > APOE2 .”
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- Authors
- Bien-Ly, N., Andrews-Zwilling, Y., Xu, Q., Bernardo, A., Wang, C., & Huang, Y.
- Affiliations
- Gladstone Institute of Neurological Disease and
- Gladstone Institutes (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-02-22
- Volume
- 108
- Issue
- 10
- Pages
- 4236-4241
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3053957
- OpenAlex
- W2089187276
- Cited by
- 71
- References
- 11
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 1 · 2023: 1 · 2022: 6 · 2021: 2 · 2020: 3 · 2019: 7 · 2018: 7 · 2017: 4 · 2016: 7 · 2015: 5 · 2014: 5 · 2013: 5 · 2012: 8
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Gladstone Institutes
- National Institutes of Health (1c06rr018928-01)
- National Institute on Aging (P01AG022074)
- National Institute of Neurological Disorders and Stroke (P30NS065780)
- National Center for Research Resources (C06RR18928, C06-RR-018928)
- Topics
- Health Sciences › Medicine › Physiology › 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
- APOE ε4, amyloid-beta clearance, amyloid-beta deposition, Alzheimer's disease, APOE3, amyloid-beta oligomers, behavioral deficits, hippocampus
- MeSH terms
- Animals, Behavior, Animal, Humans, Neurons, Protein Binding, Amyloid beta-Peptides, Mice, Apolipoprotein E4
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