Abstract
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 hydrolyze amyloid precursor protein (APP), the precursor of Aβ. In adipose tissue, PPARγ agonists can inhibit the phosphorylation of PPARγ by inhibiting cyclin-dependent kinase 5 (CDK5), which in turn affects the expression of target genes regulated by PPARγ. PPARγ agonists may also exert inhibitory effects on the phosphorylation of PPARγ in the brain, thereby affecting the expression of the aforementioned PPARγ target genes and reducing Aβ levels. The present study confirmed this hypothesis by showing that PPARγ agonist pioglitazone attenuated the neuronal apoptosis of primary rat hippocampal neurons induced by Aβ1–42, downregulated CDK5 expression, weakened the binding of CDK5 to PPARγ, reduced PPARγ phosphorylation, increased the expression of PPARγ and IDE, decreased the expression of BACE1, reduced APP production, and downregulated intraneuronal Aβ1–42 levels. These effects were inhibited by the PPARγ antagonist GW9662. After CDK5 silencing with CDK5 shRNA, the above effect of pioglitazone was not observed, except when upregulating the expression of PPARγ in Aβ1–42 treated neurons. In conclusion, this study demonstrated that pioglitazone could inhibit the phosphorylation of PPARγ in vitro by inhibiting CDK5 expression, which in turn affected the expression of PPARγ target genes Ide and Bace1, thereby promoting Aβ degradation and reducing Aβ production. This reduced Aβ levels in the brain, thereby exerting neuroprotective effects in an AD model.
Highlights
Excessive accumulation of β amyloid (Aβ) in the brain is a key pathological change in Alzheimer’s disease (AD; Tanzi et al, 2004), which can lead to neurofibrillary tangles (Bloom, 2014), inflammation (McGeer and McGeer, 2013), synaptic dysfunction (Skaper et al, 2017), oxidative stress (Butterfield et al, 2013), and neuronal apoptosis (Saad et al, 2015)
It is established that peroxisome proliferatoractivated receptor γ (PPARγ) agonists can inhibit PPARγ phosphorylation induced by cyclin-dependent kinase 5 (CDK5) in adipose tissue and that this effect can be inhibited by GW9662 (Choi et al, 2010)
In order to verify whether pioglitazone acted directly on CDK5 or PPARγ to inhibit Aβ1–42 induced apoptosis of hippocampal neurons, we tested the effect of pioglitazone on neuronal apoptosis induced by Aβ1–42 after silencing CDK5 expression with CDK5 short hairpin RNA (shRNA)
Summary
Excessive accumulation of β amyloid (Aβ) in the brain is a key pathological change in Alzheimer’s disease (AD; Tanzi et al, 2004), which can lead to neurofibrillary tangles (Bloom, 2014), inflammation (McGeer and McGeer, 2013), synaptic dysfunction (Skaper et al, 2017), oxidative stress (Butterfield et al, 2013), and neuronal apoptosis (Saad et al, 2015). Pioglitazone reduced the elevated levels of Aβ in the brain in a rat model of insulin resistance (Luo et al, 2011) and improved learning and memory function in transgenic animals with AD (Papadopoulos et al, 2013). The mechanisms of action of PPARγ agonists in reducing Aβ remain unclear
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