Activation of PPARα enhances astroglial uptake and degradation of β-amyloid.
Activation of PPARα enhances astroglial uptake and degradation of β-amyloid.
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DOI：
10.1126/scisignal.abg4747
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发表时间：
2021-10-26
影响因子：
7.3
通讯作者：
Pahan K
中科院分区：
文献类型：
--
作者：
Raha S;Ghosh A;Dutta D;Patel DR;Pahan K
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 biogenesis 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.
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DOI：
10.4049/jimmunol.1102624
发表时间：
2012-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Corbett GT;Roy A;Pahan K
通讯作者：
Pahan K
影响因子：
6.2
作者：
Khasnavis, Saurabh;Pahan, Kalipada
通讯作者：
Pahan, Kalipada
影响因子：
4.4
作者：
Jana, Malabendu;Jana, Arundhati;Pahan, Kalipada
通讯作者：
Pahan, Kalipada
影响因子：
8.8
作者：
Carey KL;Paulus GLC;Wang L;Balce DR;Luo JW;Bergman P;Ferder IC;Kong L;Renaud N;Singh S;Kost-Alimova M;Nyfeler B;Lassen KG;Virgin HW;Xavier RJ
通讯作者：
Xavier RJ
DOI：
10.1073/pnas.1705536114
发表时间：
2017-10-24
影响因子：
11.1
作者：
Kundu, Madhuchhanda;Roy, Avik;Pahan, Kalipada
通讯作者：
Pahan, Kalipada