Activation of PPARα enhances astroglial uptake and degradation of β-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 (Aβ). 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 α (PPARα)–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 Aβ from the extracellular space and its subsequent degradation in astrocytes through a PPARα-dependent pathway. GFB-RA stimulated the abundance of both low-density lipoprotein receptor (LDLR) and TFEB in astrocytes through PPARα. LDLR was critical for Aβ 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 PPARα, oral administration of GFB-RA switched astroglial activation to a neuroprotective state, lowered Aβ 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 PPARα in stimulating astroglial uptake and degradation of Aβ and suggest possible repurposing of GFB-RA combination therapy for AD.