Neuronal ROS-Induced Glial Lipid Droplet Formation is Altered by Loss of Alzheimer's Disease-Associated Genes
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Abstract
A growing list of Alzheimer's disease (AD) genetic risk factors is being identified, but the contribution of each variant to disease mechanism remains largely unknown. We have previously shown that elevated levels of reactive oxygen species (ROS) induces lipid synthesis in neurons leading to the sequestration of peroxidated lipids in glial lipid droplets (LD), delaying neurotoxicity. This neuron-to-glia lipid transport is APOD/E-dependent. To identify proteins that modulate these neuroprotective effects, we tested the role of AD risk genes in ROS-induced LD formation and demonstrate that several genes impact neuroprotective LD formation, including homologs of human ABCA1 , ABCA7 , VLDLR , VPS26 , VPS35 , AP2A , PICALM , and CD2AP Our data also show that ROS enhances Aβ42 phenotypes in flies and mice. Finally, a peptide agonist of ABCA1 restores glial LD formation in a humanized APOE4 fly model, highlighting a potentially therapeutic avenue to prevent ROS-induced neurotoxicity. This study places many AD genetic risk factors in a ROS-induced neuron-to-glia lipid transfer pathway with a critical role in protecting against neurotoxicity.
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Lipid droplets (LDs) have important roles in ageing and Alzheimer's disease (AD).
“Moreover, LDs—cellular organelles containing lipids such as glycerolipids and cholesterol—were recently found to have important roles in ageing and Alzheimer's disease (AD)10–15.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [13]
PICALM has been shown to be involved in lipid/cholesterol metabolism in Drosophila glia and HEK293 cells.
“Although PICALM has been shown to be involved in lipid/cholesterol metabolism in Drosophila glia and HEK293 cells13,36”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [13]
PICALM has been shown to promote neuron-astrocyte lipid transfer in Drosophila and rat astrocytes.
“PICALM has been shown to promote neuron–astrocyte lipid transfer in Drosophila and rat astrocytes13.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [13]
PICALM's role in lipid/cholesterol metabolism has been reported in Drosophila glia and HEK293 cells.
“its role in lipid/cholesterol metabolism has been reported in Drosophila glia and HEK293 cells13,36”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [13]
In Drosophila and rat astrocytes, PICALM is required for storing peroxidated lipids sourced from neurons.
“In Drosophila and rat astrocytes, PICALM is required for storing peroxidated lipids sourced from neurons13.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [13]
Lipid droplets impact antigen presentation on astrocytes as well as cell non-autonomous effects on neuronal oxidative stress.
“These lipid droplets impact antigen presentation on astrocytes30 as well as cell non-autonomous effects on neuronal oxidative stress20,21.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [21]
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- Authors
- Moulton, M. J., Barish, S., Ralhan, I., Chang, J., Goodman, L. D., Harland, J. G., Marcogliese, P. C., Johansson, J. O., Ioannou, M. S., & Bellen, H. J.
- Affiliations
- Baylor College of Medicine (US)
- University of Alberta (CA)
- Artery Therapeutics, Inc., San Ramon, CA 94583;
- Corresponding author
- Bellen, Hugo J.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2021-12-23
- Volume
- 118
- Issue
- 52
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC8719885
- OpenAlex
- W4225897733
- Cited by
- 180
- References
- 29
- Citations by year
- 2026: 29 · 2025: 50 · 2024: 45 · 2023: 35 · 2022: 19 · 2021: 2
- FWCI
- 15.84
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- SSRN Electronic Journal (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103555, U54HD083092)
- Texas Alzheimer's Research and Care Consortium (2018-05-11-II)
- HHS | National Institutes of Health (T32 GM07526-41, T32 NS043124-18)
- Canadian HIV Trials Network, Canadian Institutes of Health Research (MFE-164712, 173321)
- Heart and Stroke Foundation of Canada (170722)
- Alzheimer Society of Alberta and Northwest Territories (N/A)
- Howard Hughes Medical Institute (N/A)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, lipid droplets, reactive oxygen species, glial cells, APOE ε4, neurodegeneration, Drosophila
- MeSH terms
- Alzheimer Disease, Animals, Drosophila, Female, Humans, Male, Neuroglia, Neurons, Reactive Oxygen Species, Neuroprotective Agents, Mice, Genome-Wide Association Study, Lipid Droplets
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