Neuron-Specific Apolipoprotein E4 Proteolysis Is Associated with Increased Tau Phosphorylation in Brains of Transgenic Mice
Open accessAbstract
Apolipoprotein E (apoE) is found in amyloid plaques and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains, but its role in their pathogenesis is unclear. Previously, we found C-terminal-truncated fragments of apoE in AD brains and showed that such fragments can cause neurodegeneration and can induce NFT-like inclusions in cultured neuronal cells and in transgenic mice. Here, we analyzed apoE fragmentation in brain tissue homogenates from transgenic mice expressing apoE3 or apoE4 in neurons [neuron-specific enolase (NSE)-apoE] or astrocytes [glial fibrillary acidic protein (GFAP)-apoE] by Western blotting. The C-terminal-truncated fragments of apoE accumulated, in an age-dependent manner, in the brains of NSE-apoE4 and, to a significantly lesser extent, NSE-apoE3 mice; however, no fragments were detected in GFAP-apoE3 or GFAP-apoE4 mice. In NSE-apoE mice, the pattern of apoE fragmentation resembled that seen in AD brains, and the fragmentation was specific for certain brain regions, occurring in the neocortex and hippocampus, which are vulnerable to AD-related neurodegeneration, but not in the less vulnerable cerebellum. Excitotoxic challenge with kainic acid significantly increased apoE fragmentation in NSE-apoE4 but not NSE-apoE3 mice. Phosphorylated tau (p-tau) also accumulated in an age-dependent manner in NSE-apoE4 mice and, to a much lesser extent, in NSE-apoE3 mice but not in GFAP-apoE3 or GFAP-apoE4 mice. Intraneuronal p-tau inclusions in the hippocampus were prominent in 21-month-old NSE-apoE4 mice but barely detectable in NSE-apoE3 mice. Thus, the accumulation of potentially pathogenic C-terminal-truncated fragments of apoE depends on both the isoform and the cellular source of apoE. Neuron-specific proteolytic cleavage of apoE4 is associated with increased phosphorylation of tau and may play a key role in the development of AD-related neuronal deficits.
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APOE4 exacerbates AD-related pathologies, including amyloid-beta plaques, Tau tangles, neurodegeneration and neuroinflammation.
“It exacerbates AD-related pathologies, including amyloid-beta (Aβ) plaques, Tau tangles, neurodegeneration and neuroinflammation4–16.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [8]
The Introduction (page not provided) discusses amyloid-beta plaque formation as a proposed APOE4 mechanism and reports neurodegeneration and NFT-like inclusions associated with apoE fragments. The Results section on p-tau-containing inclusions (page not provided) finds more such inclusions in apoE4 than apoE3 mice. The paper does not establish that APOE4 exacerbates amyloid-beta plaques, and the passages found do not address neuroinflammation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe L28P mutation induces serious folding defects on the protein, leading to a functional phenotype demonstrated previously with a heavily truncated apoE4 proteolytic fragment similar to apoE4 fragments proposed to appear early in the pathogenetic process of Alzheimer disease.
“The mutation induces serious folding defects on the protein, leading to a functional phenotype demonstrated previously with a heavily truncated apoE4 proteolytic fragment similar to apoE4 fragments proposed to appear early in the pathogenetic process of AD (15).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [15]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredNot all apoE4 forms found in the brains of AD patients are equally bioactive, and specific apoE4 forms may be involved in processes associated with AD pathogenesis.
“These and other findings suggest that not all apoE4 forms found in the brains of AD patients are equally bioactive and that specific apoE4 forms may be involved in processes associated with AD pathogenesis (10, 14 -17).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [15]
ApoE4 fragmentation occurs in a brain region-dependent way, preferentially in the neocortex and hippocampus of NSE-ApoE4 transgenic mice.
“ApoE4 fragmentation occurs in a brain region-dependent way, preferentially in the neocortex and hippocampus of neuron-specific enolase (NSE)-ApoE4 transgenic mice”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [30]
In rat hippocampal neurons, ApoE4 caused increase in basal mitochondrial Ca2+ levels and exacerbated neuronal Ca2+ entry in response to NMDAR activation, correlated with neurotoxicity.
“ApoE4 was demonstrated to cause an increase in basal mitochondrial Ca2+ levels and also an exacerbated neuronal Ca2+ entry in response to N-methyl-D-aspartate receptor (NMDAR) activation, which was correlated with neurotoxicity [30].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [30]
The Results section on excitotoxic challenge reports increased apoE4 fragmentation after kainic acid treatment in transgenic mice, not calcium measurements in rat hippocampal neurons. A search for basal mitochondrial Ca2+, NMDAR-evoked Ca2+ entry, and their correlation with neurotoxicity found no passage addressing those claims in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
The apoE4 domain interaction renders apoE4 more susceptible to proteolytic cleavage, resulting in the generation of neurotoxic apoE4 fragments.
“Importantly, this domain interaction renders apoE4 to be more susceptible to proteolytic cleavage, resulting in the generation of neurotoxic apoE4 fragments [20–22].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [20]
ApoE4 is highly susceptible to neuron-specific proteolysis, which generates neurotoxic fragments.
“As mentioned above, apoE4 is highly susceptible to neuron-specific proteolysis, which generates neurotoxic fragments [20, 77–79].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [20]
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- Authors
- Brecht, W. J., Harris, F. M., Chang, S., Tesseur, I., Yu, G.-Q., Xu, Q., Dee Fish, J., Wyss-Coray, T., Buttini, M., Mucke, L., Mahley, R. W., & Huang, Y.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Huang, Yadong
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-03-10
- Volume
- 24
- Issue
- 10
- Pages
- 2527-2534
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6729489
- OpenAlex
- W2156998090
- Cited by
- 403
- References
- 70
- Citations by year
- 2026: 8 · 2025: 24 · 2024: 20 · 2023: 21 · 2022: 17 · 2021: 29 · 2020: 23 · 2019: 27 · 2018: 14 · 2017: 16 · 2016: 22 · 2015: 13 · 2014: 25 · 2013: 18 · 2012: 16
- FWCI
- 9.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- MetLife Foundation
- National Institutes of Health (AG‐022074, AG11385)
- National Institute on Aging (R01 AG11385, P01AG022074, R01AG011385)
- National Institute of Neurological Disorders and Stroke (R21NS046465)
- 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, apolipoprotein E3, tau phosphorylation, Alzheimer's disease, neuron-specific enolase, glial fibrillary acidic protein, transgenic mice, neurofibrillary tangles, amyloid plaques, excitotoxicity, kainic acid, hippocampus, neocortex, cerebellum, astrocytes, neurons
- MeSH terms
- Aging, Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Brain, Brain Chemistry, Female, Glial Fibrillary Acidic Protein, Humans, Kainic Acid, Mice, Transgenic, Neurons, Neurotoxins, Peptide Fragments, Phosphopyruvate Hydratase, Phosphorylation, Promoter Regions, Genetic, tau Proteins, Gene Targeting, Mice, Apolipoprotein E3, Apolipoprotein E4
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