Presenter of 3 Presentations
NUTRITIONAL METABOLISM AND CEREBRAL BIOENERGETICS IN ALZHEIMER’S DISEASE AND RELATED DEMENTIAS
CAVEOLIN-1 PROMOTES ABCA1 DEGRADATION IN APOE4 ASTROCYTES
Abstract
Aims
ATP-binding cassette transporters A1 (ABCA1) has important roles in regulating cholesterol homeostasis in the brain through its interaction with ApoE to form ApoE lipoprotein particles. We previously reported that ApoE4 decreases membrane ABCA1 levels and cholesterol efflux function in astrocytes. Our aims are to identify the mechanisms of how ApoE4 induces less astrocytic ABCA1 activity.
Methods
ABCA1 binding protein complexes from ABCA1-overexpressing cells treated with recombinant ApoE3 (rE3) or ApoE4 (rE4) proteins and performed proteomic analysis to uncover targets that mediate ABCA1 degradation in ApoE4. Target proteins were validated and then investigated in single cells isolated from mouse brains, cortical and hippocampal mouse brains, and human brains that differed by APOE genotype.
Results
The screen identified caveolin-1 and the adaptor protein 2 beta 1 (AP2B1) proteins which can bind to ABCA1 and promote ABCA1 degradation. Protein expression of Caveolin-1 but not AP2B1 was greater in mouse and human cortex with APOE4 genotype than APOE3 genotype. Single-cell isolation from mouse brains confirmed these changes are observed in astrocytes but not microglial or neuron-enriched cells. Knocking down of caveolin-1 impaired ABCA1 mediated cholesterol efflux in astrocytes. However, cholesterol accumulation in astrocytes induced ABCA1 degradation, and this was partially rescued by caveolin-1 knocking down or inhibition. In human brains, the amount of detergent-insoluble ABCA1 and caveolin-1 proteins were positively correlated in both ApoE3 and ApoE4 genotypes.
Conclusions
Our findings support that ApoE4 promotes ABCA1 degradation partly through a caveolin-1-dependent endocytosis pathway, which is regulated by cholesterol accumulation in cells. The increase in expression of caveolin-1 in astrocytes reflects cholesterol accumulation that paradoxically drives lower ABCA1 function, increasing the risk of AD pathology.