Guoyuan Qi, United States of America
University of Arizona Center for Innovation in Brain ScienceAuthor Of 1 Presentation
APOE4 IMPAIRS NEURON-ASTROCYTE COUPLING OF FATTY ACID METABOLISM
Abstract
Aims
As the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), the ε4 variant of apolipoprotein E (ApoE4) is known to perturb both lipid homeostasis and energy metabolism in brain. However, the cell type-specific mechanism of ApoE4 polymorphism in modulating brain lipid metabolism is unclear.
Methods
Using humanized ApoE3 and ApoE4 mice, here we describe a loss-of-function role of ApoE4 in regulating fatty acid (FA) metabolism across neuron and astrocyte in tandem with their distinct mitochondrial phenotypes.
Results
ApoE4 disrupts neuronal function partially by decreasing the sequestering of FA in neuronal lipid droplets (LDs). Sequestered neuronal FAs are exported and internalized by astrocytes, with ApoE4 in either cell types diminishing the transport efficiency. In ApoE4 astrocytes, increased mitochondrial fission underlies a metabolic shift towards enhanced glucose metabolism and reduced mitochondrial β-oxidation capacity, which further elicits astrocytic LD accumulation. Importantly, diminished capacity of ApoE4 astrocytes in eliminating neuronal lipids and performing FA degradation accounts for their compromised metabolic- and synaptic support to neurons.
Conclusions
These data support the coupling of neuron lipid homeostasis and astrocytic FA degradation with cell type-specific mitochondrial function, which is essential to protect neurons from energy deficit and lipotoxicity. Our findings reveal the mechanistic basis of ApoE4 in disrupting brain lipid homeostasis and bioenergetic capacity, which could underlie the accelerated lipid dysregulation, exacerbated energy deficits, and increased AD risk for ApoE4 carriers.