Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice
Open accessAbstract
Apolipoprotein (apo) E4 is expressed in many types of brain cells, is associated with age-dependent decline of learning and memory in humans, and is the major genetic risk factor for AD. To determine whether the detrimental effects of apoE4 depend on its cellular sources, we generated human apoE knock-in mouse models in which the human APOE gene is conditionally deleted in astrocytes, neurons, or GABAergic interneurons. Here we report that deletion of apoE4 in astrocytes does not protect aged mice from apoE4-induced GABAergic interneuron loss and learning and memory deficits. In contrast, deletion of apoE4 in neurons does protect aged mice from both deficits. Furthermore, deletion of apoE4 in GABAergic interneurons is sufficient to gain similar protection. This study demonstrates a detrimental effect of endogenously produced apoE4 on GABAergic interneurons that leads to learning and memory deficits in mice and provides a novel target for drug development for AD related to apoE4.
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Neurons synthesize and secrete as much as 20% of brain ApoE under physiological conditions.
“neurons were found to synthesize and secrete as much as 20% of brain ApoE under physiological conditions (Knoferle et al., 2014)”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Knoferle et al., 2014
The Results section (page unavailable) reports that deleting APOE in neurons reduced total ApoE protein by about 20% in mouse cortex, supporting a neuronal contribution to ApoE levels. The paper does not establish that neurons secrete that amount, and its hippocampal estimates differ by ApoE variant; the claim generalizes the cortical finding to brain ApoE. (LLM, conf=0.87)
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- Authors
- Knoferle, J., Yoon, S. Y., Walker, D., Leung, L., Gillespie, A. K., Tong, L. M., Bien-Ly, N., & Huang, Y.
- Affiliations
- Gladstone Institutes (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-10-15
- Volume
- 34
- Issue
- 42
- Pages
- 14069-14078
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4198545
- OpenAlex
- W2119616605
- Cited by
- 97
- References
- 10
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 13 · 2023: 8 · 2022: 7 · 2021: 13 · 2020: 11 · 2019: 8 · 2018: 3 · 2017: 3 · 2016: 9 · 2015: 5
- FWCI
- 3.53
- 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)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- S. D. Bechtel, Jr. Foundation and Stephen Bechtel Fund
- Hellman Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute on Aging (RF1AG047655, P01AG022074)
- National Institute of Neurological Disorders and Stroke (P30NS065780)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007470)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- APOE ε4, GABAergic interneurons, learning and memory impairment, Alzheimer's disease, astrocytes, conditional gene deletion, knock-in mice, aging, interneuron loss
- MeSH terms
- Animals, Female, Humans, Interneurons, Learning, Memory Disorders, Mice, Transgenic, Mice, Apolipoprotein E4, GABAergic Neurons
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