| First Author | Raha S | Year | 2021 |
| Journal | Sci Signal | Volume | 14 |
| Issue | 706 | Pages | eabg4747 |
| PubMed ID | 34699252 | Mgi Jnum | J:357881 |
| Mgi Id | MGI:7539656 | Doi | 10.1126/scisignal.abg4747 |
| Citation | Raha S, et al. (2021) Activation of PPARalpha enhances astroglial uptake and degradation of beta-amyloid. Sci Signal 14(706):eabg4747 |
| abstractText | 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 (Abeta). 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 (PPARalpha)-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 Abeta from the extracellular space and its subsequent degradation in astrocytes through a PPARalpha-dependent pathway. GFB-RA stimulated the abundance of both low-density lipoprotein receptor (LDLR) and TFEB in astrocytes through PPARalpha. LDLR was critical for Abeta 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 PPARalpha, oral administration of GFB-RA switched astroglial activation to a neuroprotective state, lowered Abeta 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 PPARalpha in stimulating astroglial uptake and degradation of Abeta and suggest possible repurposing of GFB-RA combination therapy for AD. |
