Activation of the amyloid cascade in apolipoprotein E4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits
Open accessAbstract
The allele E4 of apolipoprotein E (apoE4), the most prevalent genetic risk factor for Alzheimer's disease, is associated histopathologically with elevated levels of brain amyloid. This led to the suggestion that the pathological effects of apoE4 are mediated by cross-talk interactions with amyloid β peptide (Aβ), which accentuate the pathological effects of the amyloid cascade. The mechanisms underlying the Aβ-mediated pathological effects of apoE4 are unknown. We have shown recently that inhibition of the Aβ-degrading enzyme neprilysin in brains of wild-type apoE3 and apoE4 mice results in rapid and similar elevations in their total brain Aβ levels. However, the nucleation and aggregation of Aβ in these mice were markedly affected by the apoE genotype and were specifically enhanced in the apoE4 mice. We presently used the neprilysin inhibition paradigm to analyze the neuropathological and cognitive effects that are induced by apoE4 after activation of the amyloid cascade. This revealed that apoE4 stimulates isoform specifically the degeneration of hippocampal CA1 neurons and of entorhinal and septal neurons, which is accompanied by the accumulation of intracellular Aβ and apoE and with lysosomal activation. Furthermore, these neuropathological effects are associated isoform specifically with the occurrence of pronounced cognitive deficits in the ApoE4 mice. These findings provide the first in vivo evidence regarding the cellular mechanisms underlying the pathological cross talk between apoE4 and Aβ, as well as a novel model system of neurodegeneration in vivo that is uniquely suitable for studying the early stages of the amyloid cascade and the effects thereon of apoE4.
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Several recent studies provided evidence to support increased content of Aβ oligomers in the extracellular space in brains of patients with AD expressing human ApoE4 isoform, and intraneuronally in mice expressing human ApoE4 isoform after inhibition of Aβ-degrading enzyme neprilysin.
“Several recent studies provided evidence to support increased content of Ab oligomers in the extracellular space in brains of patients with AD, expressing the human ApoE4 isoform, 37,38 and intraneuronally in mice expressing human ApoE4 isoform after inhibition of Ab-degrading enzyme neprilysin.39”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [39]
The ‘Intraneuronal accumulation of Aβ and ApoE’ section reports increased Aβ staining in CA1 neurons of apoE4 mice after neprilysin inhibition, supporting the mouse finding attributed to this source (citation 39). It does not identify the intraneuronal Aβ as oligomers. The patient finding is attached to citations 37 and 38, not this paper. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn a model involving inhibition of the Aβ-degrading enzyme neprilysin, intraneuronal oligomerization and accumulation of Aβ occurred more readily in mice expressing the ApoE4 isoform than the ApoE3 isoform.
“As shown in another model involving inhibition of the Ab-degrading enzyme neprilysin, intraneuronal oligomerization and accumulation of Ab occurred more readily in mice that expressed the ApoE4 isoform than the ApoE3 isoform.39”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [39]
The Discussion (page unavailable) reports that neprilysin inhibition led to intraneuronal Aβ accumulation in ApoE4 but not ApoE3 mice. The Introduction mentions enhanced Aβ nucleation and aggregation in ApoE4 mice, but our copy does not establish that oligomerization occurred intraneuronally in this model. (LLM, conf=0.88)
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- Authors
- Belinson, H., Lev, D., Masliah, E., & Michaelson, D. M.
- Affiliations
- Tel Aviv University (IL)
- University of California San Diego (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-04-30
- Volume
- 28
- Issue
- 18
- Pages
- 4690-4701
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3844816
- OpenAlex
- W2085235587
- Cited by
- 101
- References
- 49
- Citations by year
- 2025: 3 · 2024: 7 · 2023: 1 · 2022: 8 · 2021: 4 · 2020: 5 · 2019: 5 · 2018: 6 · 2017: 2 · 2016: 10 · 2015: 3 · 2014: 3 · 2013: 9 · 2012: 10
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG‐022074, AG10435)
- National Institute on Aging (P01AG010435, AG022074, P01AG022074, AG48440, AG10435)
- 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 hypothesis, amyloid-beta, neprilysin inhibition, lysosomal activation, neurodegeneration, cognitive impairment, CA1 pyramidal neurons, entorhinal cortex, septal neurons, amyloid-beta aggregation, Alzheimer's disease, transgenic mice
- MeSH terms
- Analysis of Variance, Animals, Cognition Disorders, Disease Models, Animal, Exploratory Behavior, Hippocampus, Learning, Lysosomes, Mice, Inbred C57BL, Mice, Transgenic, Neuropsychological Tests, Synapses, Water Deprivation, Neprilysin, Amyloid beta-Peptides, Drug Delivery Systems, Neurodegenerative Diseases, Microscopy, Electron, Transmission, Mice, Apolipoprotein E3, Apolipoprotein E4
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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