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 Aβ 1–42 , 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 Aβ 1–42 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 Aβ 1–42 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.
Background and PurposeThe present study was designed to examine the effects of ginsenoside Rg1 on expression of peroxisome proliferator-activated receptor γ (PPARγ) and insulin-degrading enzyme (IDE) in the hippocampus of rat model of Alzheimer's disease (AD) to determine how ginsenoside Rg1 (Rg1) decreases Aβ levels in AD.Experimental ApproachExperimental AD was induced in rats by a bilateral injection of 10 µg soluble beta-amyloid peptide 1–42 (Aβ1–42) into the CA1 region of the hippocampus, and the rats were treated with Rg1 (10 mg·kg−1, intraperitoneally) for 28 days. The Morris water maze was used to test spatial learning and memory performance. Hematoxylin-eosin staining was performed to analyze the hippocampal histopathological damage. Immunohistochemistry, western blotting, and real-time PCR were used to detect Aβ1–42, PPARγ, and insulin-degrading enzyme (IDE) expression in the hippocampus.Key ResultsInjection of soluble Aβ1–42 into the hippocampus led to significant dysfunction of learning and memory, hippocampal histopathological abnormalities and increased Aβ1–42 levels in the hippocampus. Rg1 treatment significantly improved learning and memory function, attenuated hippocampal histopathological abnormalities, reduced Aβ1–42 levels and increased PPARγ and IDE expression in the hippocampus; these effects of Rg1 could be effectively inhibited by GW9662, a PPARγ antagonist.Conclusions and ImplicationsGiven that PPARγ can upregulate IDE expression and IDE can degrade Aβ1–42, these results indicate that Rg1 can increase IDE expression in the hippocampus by upregulating PPARγ, leading to decreased Aβ levels, attenuated hippocampal histopathological abnormalities and improved learning and memory in a rat model of AD.
The accumulation of β-amyloid peptides (aβ) in the brain is a hallmark of alzheimer's disease (ad). Studies have indicated that ginsenoside rg1, a primary component of ginseng (Panax ginseng), reduces brain aβ levels in an ad model through peroxisome proliferator-activated receptor γ (PParγ), thereby regulating the expression of insulin-degrading enzyme (Ide) and β-amyloid cleavage enzyme 1 (Bace1), which are PParγ target genes. However, the effects of ginsenoside rg1 on PParγ remain unclear. Since cyclin-dependent kinase 5 (cdK5) mediates PParγ phosphorylation in adipose tissue, this study aimed to investigate whether ginsenoside rg1 regulates PParγ target genes and reduces aβ levels by inhibiting PParγ phosphorylation through the cdK5 pathway. in the present study, a model of ad was established by treating primary cultured rat hippocampal neurons with aβ 1-42. The cells were pretreatment with ginsenoside rg1 and roscovitine, a cdK5-inhibitor, prior to the treatment with aβ 1-42. neuronal apoptosis was detected using Tunel staining. PParγ phosphorylation and protein expression levels of PParγ, cdK5, ide, Bace1, amyloid precursor protein (aPP) and aβ 1-42 were measured by western blotting. The mrna expression levels of PParγ, cdK5, ide, Bace1 and aPP were assessed using reverse transcription-quantitative Pcr. The results of the present study demonstrated that in an ad model induced by aβ 1-42 , ginsenoside Rg1 significantly decreased CDK5 expression, inhibited PParγ phosphorylation at serine 273, elevated ide expression, downregulated Bace1 and aPP expression, decreased aβ 1-42 levels and attenuated neuronal apoptosis. The cdK5 inhibitor, roscovitine, demonstrated similar effects. These results suggest that ginsenoside rg1 has neuroprotective properties and has potential for use in the treatment of ad.
Rg1 can inhibit I via MAPK in hippocampal neurons in Aβ-exposed rat brain slices.
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