Activation of PPAR alpha enhances astroglial uptake and degradation of beta-amyloid

Astrocytes are a type of glial cell that are activated in the brain tissue of patients with Alzheimer's disease to induce the accumulation of amyloid (A beta). We previously found that a combination of low-dose gemfibrozil (GFB; a drug approved to treat high cholesterol) and retinoic acid (RA; a vitamin A derivative) induces lysosomal bio-genesis through peroxisome proliferator-activated receptor alpha (PPAR alpha)-mediated transcription of the gene encoding transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy. Here, we found that the same combination (GFB-RA) enhanced the uptake of A beta from the extracellular space and its subsequent degradation in astrocytes through a PPAR alpha-dependent pathway. GFB-RA stimulated the abundance of both low-density lipoprotein receptor (LDLR) and TFEB in astrocytes through PPAR alpha. LDLR was critical for A beta uptake, whereas TFEB was critical for its degradation. GFB-RA treatment also increased autophagic flux and lysosomal activity in astrocytes. Consistent with these effects and in a manner dependent on astroglial PPAR alpha, oral administration of GFB-RA switched astroglial activation to a neuroprotective state, lowered A beta burden in the brain, and improved spatial learning and memory in the 5XFAD mouse model of Alzheimer's disease. These findings uncover a new function of PPAR alpha in stimulating astroglial uptake and degradation of A beta and suggest possible repurposing of GFB-RA combination therapy for AD.