Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice
Open accessAbstract
Alzheimer's disease (AD) is the most common form of dementia in individuals over the age of 65 years. The most prevalent genetic risk factor for AD is the ε4 allele of apolipoprotein E (ApoE4), and novel AD treatments that target ApoE are being considered. One unresolved question in ApoE biology is whether ApoE is necessary for healthy brain function. ApoE knock-out (KO) mice have synaptic loss and cognitive dysfunction; however, these findings are complicated by the fact that ApoE knock-out mice have highly elevated plasma lipid levels, which may independently affect brain function. To bypass the effect of ApoE loss on plasma lipids, we generated a novel mouse model that expresses ApoE normally in peripheral tissues, but has severely reduced ApoE in the brain, allowing us to study brain ApoE loss in the context of a normal plasma lipid profile. We found that these brain ApoE knock-out (bEKO) mice had synaptic loss and dysfunction similar to that of ApoE KO mice; however, the bEKO mice did not have the learning and memory impairment observed in ApoE KO mice. Moreover, we found that the memory deficit in the ApoE KO mice was specific to female mice and was fully rescued in female bEKO mice. Furthermore, while the AMPA/NMDA ratio was reduced in ApoE KO mice, it was unchanged in bEKO mice compared with controls. These findings suggest that plasma lipid levels can influence cognition and synaptic function independent of ApoE expression in the brain. SIGNIFICANCE STATEMENT One proposed treatment strategy for Alzheimer's disease (AD) is the reduction of ApoE, whose ε4 isoform is the most common genetic risk factor for the disease. A major concern of this strategy is that an animal model of ApoE deficiency, the ApoE knock-out (KO) mouse, has reduced synapses and cognitive impairment; however, these mice also develop dyslipidemia and severe atherosclerosis. Here, we have shown that genetic restoration of plasma ApoE to wild-type levels normalizes plasma lipids in ApoE KO mice. While this does not rescue synaptic loss, it does completely restore learning and memory in the mice, suggesting that both CNS and plasma ApoE are independent parameters that affect brain health.
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APOE is not transferred over the blood brain barrier, suggesting astrocytes are the main contributor of APOE in the brain.
“However, APOE is not transferred over the blood brain barrier (Huynh et al, 2019; Lane-Donovan et al, 2016) suggesting that astrocytes are the main contributor of APOE in the brain (Boyles et al, 1985; Zhang et al, 2014).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Lane-Donovan et al, 2016
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- Authors
- Lane-Donovan, C., Wong, W. M., Durakoglugil, M. S., Wasser, C. R., Jiang, S., Xian, X., & Herz, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Freiburg (DE)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-09-28
- Volume
- 36
- Issue
- 39
- Pages
- 10141-10150
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5039258
- OpenAlex
- W2525194959
- Cited by
- 115
- References
- 15
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 17 · 2023: 13 · 2022: 18 · 2021: 15 · 2020: 7 · 2019: 11 · 2018: 6 · 2017: 10 · 2016: 1
- FWCI
- 6.39
- 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
- American Health Assistance Foundation
- Ted Nash Long Life Foundation
- National Institutes of Health
- National Institute on Aging (RF1AG053391, F30AG047799)
- National Heart, Lung, and Blood Institute (R37HL063762)
- National Institute of General Medical Sciences (T34GM008073)
- National Institute of Neurological Disorders and Stroke (R01NS093382)
- 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
- apolipoprotein E, APOE ε4, Alzheimer's disease, synaptic loss, learning and memory, sex differences, plasma lipids, dyslipidemia, AMPA/NMDA ratio, cognitive impairment
- MeSH terms
- Animals, Apolipoproteins E, Cognition, Cognition Disorders, Female, Lipids, Male, Mice, Transgenic, Synapses, Mice, Knockout, Mice
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