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Pioglitazone Reduces ? Amyloid Levels via Inhibition of PPAR? Phosphorylation in a Neuronal Model of Alzheimer's Disease.

ABSTRACT: It has been demonstrated that peroxisome proliferator-activated receptor ? (PPAR?) can regulate the transcription of its target gene, insulin-degrading enzyme (IDE), and thus enhance the expression of the IDE protein. The protein can degrade ? amyloid (A?), a core pathological product of Alzheimer's disease (AD). PPAR? can also regulate the transcription of other target gene, ?-amyloid cleavage enzyme 1 (BACE1), and thus inhibit the expression of the BACE1 protein. BACE1 can hydrolyze amyloid precursor protein (APP), the precursor of A?. In adipose tissue, PPAR? agonists can inhibit the phosphorylation of PPAR? by inhibiting cyclin-dependent kinase 5 (CDK5), which in turn affects the expression of target genes regulated by PPAR?. PPAR? agonists may also exert inhibitory effects on the phosphorylation of PPAR? in the brain, thereby affecting the expression of the aforementioned PPAR? target genes and reducing A? levels. The present study confirmed this hypothesis by showing that PPAR? agonist pioglitazone attenuated the neuronal apoptosis of primary rat hippocampal neurons induced by A?1-42, downregulated CDK5 expression, weakened the binding of CDK5 to PPAR?, reduced PPAR? phosphorylation, increased the expression of PPAR? and IDE, decreased the expression of BACE1, reduced APP production, and downregulated intraneuronal A?1-42 levels. These effects were inhibited by the PPAR? antagonist GW9662. After CDK5 silencing with CDK5 shRNA, the above effect of pioglitazone was not observed, except when upregulating the expression of PPAR? in A?1-42 treated neurons. In conclusion, this study demonstrated that pioglitazone could inhibit the phosphorylation of PPAR? in vitro by inhibiting CDK5 expression, which in turn affected the expression of PPAR? target genes Ide and Bace1, thereby promoting A? degradation and reducing A? production. This reduced A? levels in the brain, thereby exerting neuroprotective effects in an AD model.

SUBMITTER: Quan Q

PROVIDER: S-EPMC6650543 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Pioglitazone Reduces β Amyloid Levels via Inhibition of PPARγ Phosphorylation in a Neuronal Model of Alzheimer's Disease.

Quan Qiankun Q Qian Yihua Y Li Xi X Li Ming M

Frontiers in aging neuroscience 20190717

It has been demonstrated that peroxisome proliferator-activated receptor γ (PPARγ) can regulate the transcription of its target gene, insulin-degrading enzyme (IDE), and thus enhance the expression of the IDE protein. The protein can degrade β amyloid (Aβ), a core pathological product of Alzheimer's disease (AD). PPARγ can also regulate the transcription of other target gene, β-amyloid cleavage enzyme 1 (BACE1), and thus inhibit the expression of the BACE1 protein. BACE1 can hydrol ...[more]

PMID: 31379559

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Pioglitazone Reduces ? Amyloid Levels via Inhibition of PPAR? Phosphorylation in a Neuronal Model of Alzheimer's Disease.

Publications

Pioglitazone Reduces β Amyloid Levels <i>via</i> Inhibition of PPARγ Phosphorylation in a Neuronal Model of Alzheimer's Disease.

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