Abstract
Amyloid-β (Aβ) accumulation in the brain is a pathological feature of Alzheimer’s disease (AD) and enhancing Aβ clearance is a potential therapeutic strategy. Pioglitazone is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist and is widely used to treat type 2 diabetes. We previously reported that low-dose pioglitazone increased the expression of low-density lipoprotein receptor-related protein 1 (LRP1), which upregulates the clearance of Aβ, using human brain microvascular endothelial cells. We investigated whether low-dose pioglitazone can rescue the pathological phenotype and memory impairment in senescence-accelerated mouse prone-8 (SAMP8) mice by increasing LRP1 levels. SAMP8 mice were treated with vehicle or pioglitazone in dosages of 2 or 5 mg/kg/day for 7 weeks. In the water maze test, 2 mg/kg/day of pioglitazone significantly attenuated the increased escape latency in SAMP8 mice (p = 0.026), while 5 mg/kg/day of treatment did not. Compared with vehicle treatment, the hippocampi of SAMP8 mice with 2 mg/kg/day of pioglitazone exhibited fewer Aβ deposits and reduced Aβ1–40 levels, along with elevated LRP1 expression (p = 0.005). Collectively, our results proposed that a new therapeutic application of the PPAR-γ agonist for AD treatment should be considered at a lower dose than the conventional dose used to treat diabetes.
Highlights
Amyloid-β (Aβ) accumulation in the brain is a pathological feature of Alzheimer’s disease (AD) and enhancing Aβ clearance is a potential therapeutic strategy
Considering that a 7-day rosiglitazone oral treatment results in concentrations of 260–450 nM in the human brain[30], this unusual dose-response in vitro study suggests that a new therapeutic application of peroxisome proliferatoractivated receptor-γ (PPAR-γ) agonist for AD should be considered at a lower dose than the conventional dose used to treat diabetes
We investigated whether pioglitazone could upregulate lipoprotein receptorrelated protein 1 (LRP1) expression, accompanied by reduction of Aβ plaque deposition in a mouse model of sporadic AD, senescence-accelerated mouse prone-8 (SAMP8)
Summary
Amyloid-β (Aβ) accumulation in the brain is a pathological feature of Alzheimer’s disease (AD) and enhancing Aβ clearance is a potential therapeutic strategy. Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, is widely used to treat hyperglycaemia in type 2 diabetes This PPAR-γ agonist is a potential candidate to treat AD, as it has been shown to improve memory dysfunction and reduce accumulation of Aβ in previous animal studies of AD20–23. Moon et al reported that low-dose PPAR-γ agonist treatment, but not the conventional doses, exhibits an Aβ-clearing effect by increasing LRP1 in human brain microvascular endothelial cells (HBMECs)[29]. Another PPAR-γ agonist, rosiglitazone, upregulates mRNA and protein levels of LRP1 in addition to LRP1 promoter activity, and increases Aβ uptake via LRP1 in HBMECs29. Our finding suggests a theoretical basis for the use of pioglitazone in treating AD, by demonstrating the efficacy of low-dose pioglitazone in the improvement of memory impairment and Aβ pathology-related LRP1 expression in a mouse model of AD
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