ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Aβ impairment of insulin signaling in an Alzheimer’s disease mouse model
Open accessAbstract
The apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer’s disease (AD). The AD brain was shown to be insulin resistant at end stage, but the interplay between insulin signaling, ApoE4 and Aβ across time and their involvement in memory decline is unclear. To investigate insulin response in the ageing mouse hippocampus, we crossed the human ApoE-targeted replacement mice with the mutant human amyloid precursor protein (APP) mice (ApoExAPP). While hippocampal Aβ levels were comparable between ApoE3xAPP and ApoE4xAPP mice at 26 weeks, insulin response was impaired in the ApoE4xAPP hippocampus. Insulin treatment was only able to stimulate insulin signaling and increased AMPA-GluR1 phosphorylation in forskolin pre-treated hippocampal slices from ApoE3xAPP mice. In ApoE4xAPP mice, insulin dysfunction was also associated with poorer spatial memory performance. Using dissociated hippocampal neuron in vitro, we showed that insulin response in ApoE3 and ApoE4 neurons increased AMPA receptor-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes and GluR1-subunit insertion. Pre-treatment of ApoE3 neurons with Aβ42 did not affect insulin-mediated GluR1 subunit insertion. However, impaired insulin sensitivity observed only in the presence of ApoE4 and Aβ42, attenuated GluR1-subunit insertion. Taken together, our results suggest that ApoE4 enhances Aβ inhibition of insulin-stimulated AMPA receptor function, which accelerates memory impairment in ApoE4xAPP mice.
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Amyloid plaque burden is higher in APP/ApoE4 mice compared with APP/ApoE3 mice.
“Because amyloid plaque burden is higher in the ApoE4 mice compared with ApoE3 mice, it is hard to rule out whether the higher amount of amyloid β in the APP/ApoE4 mice actually contributes to the insulin resistance.”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [49]
The Results section reports higher hippocampal plaque load in ApoE4xAPP than ApoE3xAPP mice at 52 and 78 weeks. It also reports no significant difference at 26 weeks, when the Discussion says insulin signaling was already impaired in ApoE4xAPP mice. The unqualified claim therefore omits an important age limitation. (LLM, conf=0.91)
Experimental — accuracy not yet measuredApoE4 enhanced amyloid β-induced impairment of insulin signaling and accelerated hippocampal-dependent cognitive deficits compared with ApoE3 in an APP mouse model expressing human ApoE isoforms.
“ApoE4 enhanced the amyloid β-induced impairment of insulin signaling and accelerated the hippocampal-dependent cognitive deficits, as compared with ApoE3 [49].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [49]
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Uddin, M. S., Kabir, M. T., Tewari, D., Mamun, A. A., Barreto, G. E., BUNGAU, S. G., Bin-Jumah, M. N., Abdel‐Daim, M. M., & Ashraf, G. M. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02065-3 · Cited by 27 · see citing works
Eskandari, S., Sajadimajd, S., Alaei, L., Soheilikhah, Z., Derakhshankhah, H., & Bahrami, G. (2021) · Neurotoxicity Research · doi:10.1007/s12640-021-00381-7 · Cited by 24 · see citing works
APOE ε4, the door to insulin‐resistant dyslipidemia and brain fog? A case study
Stoykovich, S., & Gibas, K. J. (2019) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2019.01.009 · Cited by 17 · see citing works
Jiang, C., Stewart, L. T., Kuo, H., McGilberry, W., Wall, S. B., Liang, B., van Groen, T., Bailey, S. M., Kim, Y.-I., Tipple, T. E., et al. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.05.006 · Cited by 16 · see citing works
Chan, E. S., Chen, C., Soong, T. W., & Wong, B. (2018) · NeuroMolecular Medicine · doi:10.1007/s12017-018-8480-3 · Cited by 14 · see citing works
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The Impact of APOE ɛ 4 in Alzheimer’s Disease Differs According to Age
Kim, J., Park, S., Yoo, H., Jang, H., Kim, Y., Kim, K. W., Jang, Y. K., Lee, J. S., Kim, S. T., Kim, S., et al. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170556 · Cited by 13 · see citing works
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Neuroinflammation drives APOE genotype-dependent differential expression of neprilysin
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Metabolic syndrome marks early risk for cognitive decline with APOE4 gene variation: A case study
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Alzheimers Disease-Like Neuropathology Following Exposure to Ambient Noise
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Age- and ApoE Genotype-Dependent Transcriptomic Responses to O3 in the Hippocampus of Mice
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Pinky, Neha, Kaushik, M., Tiwari, P., El‐Tanani, M., Rabbani, S. A., & Parvez, S. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1729046
- Authors
- Chan, E. S., Shetty, M. S., Sajikumar, S., Chen, C., Soong, T. W., & Wong, B.-S.
- Affiliations
- National University of Singapore (SG)
- Corresponding author
- Wong, Boon-Seng
- Venue
- Scientific Reports
- Published
- 2016-05-18
- Volume
- 6
- Issue
- 1
- Pages
- 26119-26119
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4870502
- OpenAlex
- W2403478980
- Cited by
- 39
- References
- 68
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2022: 3 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 8 · 2017: 3 · 2016: 1
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- National University of Singapore
- National University Health System (NUHSRO/2011/005/STB/B2B-01)
- Medical Research Council
- National Medical Research Council (NMRC/CBRG/0090/2015)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, Alzheimer's disease, amyloid-beta, insulin signaling, insulin resistance, hippocampus, AMPA receptors, spatial memory, APP transgenic mice, memory impairment, miniature excitatory postsynaptic currents
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Hippocampus, Humans, Insulin, Mice, Transgenic, Signal Transduction, Amyloid beta-Peptides, Receptors, AMPA, Mice, Apolipoprotein E4, Cognitive Dysfunction
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