Astrocyte lipid metabolism in brain health and neurodegeneration: from regulatory hub to maladaptive stressor.
5 affiliations
- 1Center for Innovation in Brain Science, University of Arizona, 1230 N Cherry Ave, BSRL 471, Tucson, AZ, 85721, USA.
- 2Department of Pharmacology, College of Medicine Tucson, University of Arizona, Tucson, AZ, USA.
- 3Center for Innovation in Brain Science, University of Arizona, 1230 N Cherry Ave, BSRL 471, Tucson, AZ, 85721, USA. [email protected].
- 4Department of Pharmacology, College of Medicine Tucson, University of Arizona, Tucson, AZ, USA. [email protected].
- 5Graduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, AZ, USA. [email protected].
Abstract
Neurodegenerative diseases are increasingly recognized as multicellular pathologies in which astrocytes serve as active determinants of disease onset and progression. Central to the regulatory role of astrocytes is the precise and dynamic control of brain lipid homeostasis. This review discusses a framework positioning astrocytic lipid metabolism as a key axis of both brain metabolic health and neurodegenerative processes. Under physiological conditions, astrocytes operate as the primary lipid metabolic hub, coordinating de novo cholesterol synthesis, APOE-mediated lipid transport, and the uptake and degradation of fatty acids. However, upon aging, chronic stress, and proteinopathies, these homeostatic programs undergo profound adaptation and remodeling. We detail how the breakdown of astrocytic lipid handling-driven by genetic risk factors such as APOE4 and manifesting as cholesterol dyshomeostasis, aberrant lipid droplet accumulation, impaired lipid turnover, and pro-inflammatory lipid signaling-transforms astrocytes into maladaptive reactive states and contributes to neurodegeneration. This metabolic rewiring not only deprives vulnerable neurons of essential metabolic and structural support but actively amplifies neuroinflammation and neurotoxicity. Finally, we consider therapeutic strategies aimed at restoring functional lipid flux and mitigating lipid-driven pathogenic signaling. By examining neurodegeneration through the lens of astrocytic lipid metabolism, we highlight novel conceptual paradigms for understanding neurodegeneration and emerging translational opportunities for disease interventions.
Related
- Impaired regulatory T cell mediated immune tolerance promotes neurodegeneration in glaucoma
- Adipose tissue as a systemic modulator of brain aging: mechanistic links between metabolism, inflammation and neurodegeneration
- A Common Set of Gene Regulatory Networks Links Metabolism and Growth Inhibition
- Lipid Metabolism and Ferroptosis in Cancer: Regulatory Mechanisms, Alternative Splicing, and Therapeutic Implications
- Self-Identity and Trauma- and Stressor-related Psychopathology: A Systematic Review
BibTeX
@article{wang2026astrocyte,
title = {{Astrocyte lipid metabolism in brain health and neurodegeneration: from regulatory hub to maladaptive stressor.}},
author = {Weihua Wang and Huajun Pan and Yashi Mi and Juvie Farol and Fei Yin},
journal = {Molecular neurodegeneration},
year = {2026},
month = aug,
doi = {10.1186/s13024-026-00981-x},
url = {https://europepmc.org/article/MED/42972384},
note = {CC BY},
}
RIS
TY - JOUR
TI - Astrocyte lipid metabolism in brain health and neurodegeneration: from regulatory hub to maladaptive stressor.
AU - Weihua Wang
AU - Huajun Pan
AU - Yashi Mi
AU - Juvie Farol
AU - Fei Yin
PY - 2026
DA - 2026/08/01
JO - Molecular neurodegeneration
DO - 10.1186/s13024-026-00981-x
UR - https://europepmc.org/article/MED/42972384
AB - Neurodegenerative diseases are increasingly recognized as multicellular pathologies in which astrocytes serve as active determinants of disease onset and progression. Central to the regulatory role of astrocytes is the precise and dynamic control of brain lipid homeostasis. This review discusses a framework positioning astrocytic lipid metabolism as a key axis of both brain metabolic health and neurodegenerative processes. Under physiological conditions, astrocytes operate as the primary lipid metabolic hub, coordinating de novo cholesterol synthesis, APOE-mediated lipid transport, and the uptake and degradation of fatty acids. However, upon aging, chronic stress, and proteinopathies, these homeostatic programs undergo profound adaptation and remodeling. We detail how the breakdown of astrocytic lipid handling-driven by genetic risk factors such as APOE4 and manifesting as cholesterol dyshomeostasis, aberrant lipid droplet accumulation, impaired lipid turnover, and pro-inflammatory lipid signaling-transforms astrocytes into maladaptive reactive states and contributes to neurodegeneration. This metabolic rewiring not only deprives vulnerable neurons of essential metabolic and structural support but actively amplifies neuroinflammation and neurotoxicity. Finally, we consider therapeutic strategies aimed at restoring functional lipid flux and mitigating lipid-driven pathogenic signaling. By examining neurodegeneration through the lens of astrocytic lipid metabolism, we highlight novel conceptual paradigms for understanding neurodegeneration and emerging translational opportunities for disease interventions.
SN - 1750-1326
ER -