Impaired Autophagy in APOE4 Astrocytes
Abstract
Alzheimer's disease (AD) is the most prevalent form of dementia in elderly. Genetic studies revealed allelic segregation of the apolipoprotein E (ApoE) gene in sporadic AD and in families with higher risk of AD. The mechanisms underlying the pathological effects of ApoE4 are not yet entirely clear. Several studies indicate that autophagy, which plays an important role in degradation pathways of proteins, organelles and protein aggregates, may be impaired in AD. In the present study, we investigated the effects of ApoE4 versus the ApoE3 isoform on the process of autophagy in mouse-derived astrocytes. The results obtained reveal that under several autophagy-inducing conditions, astrocytes expressing ApoE4 exhibit lower autophagic flux compared to astrocytes expressing ApoE3. Using an in situ model, we examined the role of autophagy and the effects thereon of ApoE4 in the elimination of Aβ plaques from isolated brain sections of transgenic 5xFAD mice. This revealed that ApoE4 astrocytes eliminate Aβ plaques less effectively than the corresponding ApoE3 astrocytes. Additional experiments showed that the autophagy inducer, rapamycin, enhances Aβ plaque degradation by ApoE4 astrocytes whereas the autophagy inhibitor, chloroquine, blocks Aβ plaque degradation by ApoE3 astrocytes. Taken together, these findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired autophagy may…
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APOE4 is associated with impaired autophagy in astrocytes.
“Previously, others and we have found that APOE4 is associated with impaired autophagy in astrocytes13,14, which is linked to reduced clearance of Aβ plaques and protein aggregates13,14.”
From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [13]
Impaired autophagy in APOE4 astrocytes is linked to reduced clearance of Aβ plaques and protein aggregates.
“Previously, others and we have found that APOE4 is associated with impaired autophagy in astrocytes13,14, which is linked to reduced clearance of Aβ plaques and protein aggregates13,14.”
From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [13]
Studies in other model systems have observed impaired autophagy in APOE4 astrocytes and other glia.
“Studies in other model systems have observed impaired autophagy in APOE4 astrocytes and other glia16,75,76.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [76]
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- Authors
- Simonovitch, S., Schmukler, E., Bespalko, A., Iram, T., Frenkel, D., Holtzman, D. M., Masliah, E., Michaelson, D. M., & Pinkas-Kramarski, R.
- Affiliations
- Tel Aviv University (IL)
- Washington University in St. Louis (US)
- University of California San Diego (US)
- Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel
- Corresponding author
- Michaelson, Danny M.
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2016-03-30
- Volume
- 51
- Issue
- 3
- Pages
- 915-927
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W2291070922
- Cited by
- 136
- References
- 6
- Citations by year
- 2026: 15 · 2025: 11 · 2024: 15 · 2023: 14 · 2022: 21 · 2021: 18 · 2020: 13 · 2019: 14 · 2018: 6 · 2017: 7 · 2016: 2
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, APOE ε4
- MeSH terms
- Animals, Astrocytes, Autophagy, Brain, Cells, Cultured, Central Nervous System Agents, Chloroquine, Disease Models, Animal, Humans, Mice, Transgenic, Time Factors, Amyloid beta-Peptides, Sirolimus, Apolipoprotein E3, Apolipoprotein E4, Plaque, Amyloid
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