Journal
CELL REPORTS
Volume 34, Issue 1, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108572
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Funding
- University of Arizona Center for Innovation in Brain Science startup fund
- NIA [P01AG026572]
- Arizona Alzheimer's Consortium Pilot Project
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This study reveals the detrimental effects of ApoE4 on fatty acid metabolism in neurons and astrocytes, leading to lipid accumulation and energy imbalance. ApoE4 decreases the transport efficiency of neuronal lipids, compromising metabolic and synaptic support from astrocytes to neurons.
Alzheimer's disease (AD) risk gene ApoE4 perturbs brain lipid homeostasis and energy transduction. However, the cell-type-specific mechanism of ApoE4 in modulating brain lipid metabolism is unclear. Here, we describe a detrimental role of ApoE4 in regulating fatty acid (FA) metabolism across neuron and astrocyte in tandem with their distinctive mitochondrial phenotypes. ApoE4 disrupts neuronal function by decreasing FA sequestering in lipid droplets (LDs). FAs in neuronal LDs are exported and internalized by astrocytes, with ApoE4 diminishing the transport efficiency. Further, ApoE4 lowers FA oxidation and leads to lipid accumulation in both astrocyte and the hippocampus. Importantly, diminished capacity of ApoE4 astrocytes in eliminating neuronal lipids and degrading FAs accounts for their compromised metabolic and synaptic support to neurons. Collectively, our findings reveal a mechanism of ApoE4 disruption to brain FA and bioenergetic homeostasis that could underlie the accelerated lipid dysregulation and energy deficits and increased AD risk for ApoE4 carriers.
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