Sildenafil Decreases BACE1 and Cathepsin B Levels and Reduces APP Amyloidogenic Processing in the SAMP8 Mouse

Abstract

The senescence-accelerated mouse-prone 8 (SAMP8), used as a model of aging, displays many established pathological features of Alzheimer's disease. Cognitive impairments and increased levels of hyperphosphorylated tau are found in the hippocampus of SAMP8 mice along with an increased β-secretase activity and amyloid-β (Aβ) depositions that increase in number and extent with age. Based on a previous study from our laboratory showing an amelioration of cognitive impairments and tau pathology by sildenafil, in this study we tested whether this drug could also modulate the amyloid precursor protein amyloidogenic processing in this mouse model. Our results show that the protein levels of the β-secretases β-site amyloid precursor protein cleaving enzyme 1 and cathepsin B are higher in the hippocampus of 9-month-old SAMP8 mice than those of age-matched senescence-resistant-1. Sildenafil (7.5mg/kg for 4 weeks) attenuated learning and memory impairments shown by SAMP8 mice in the passive avoidance test. The increased expression of β-site amyloid precursor protein cleaving enzyme 1 was also reduced by sildenafil, an effect paralleled to decreases in the activities of two β-site amyloid precursor protein cleaving enzyme 1 modulators, calpain and cyclin-dependent kinase 5 protein. Interestingly, sildenafil enhanced both Akt and glycogen synthase kinase-3β (ser9) phosphorylation, which could be mediating the reduction in cathepsin B levels found in the hippocampus of sildenafil-treated SAMP8 mice. Sildenafil-induced reduction in β-site amyloid precursor protein cleaving enzyme 1 and cathepsin B expression in SAMP8 mice was associated with a decrease in hippocampal Aβ42 levels which, in turn, could mediate the parallel decline in glial fibrillary acidic protein expression observed in these animals. These findings highlight the therapeutic potential of sildenafil in Alzheimer's disease pathogenesis.

The Role of NO/cGMP Signaling on Neuroinflammation: A New Therapeutic Opportunity

“…Pifarré et al [142] also showed that the presence of astrocytes forming scar-like structures around infiltrates was enhanced by sildenafil, suggesting a possible mechanism for the restriction of the leukocyte dissemination in healthy parenchyma. However, this result does not corroborate other studies showing that PDE5-Is decrease GFAP expression and astrocyte activation [89,114,127,140].…”

“…due to differences between dose, duration of treatment, and animal models. In addition, both Akt/GSK3β and p25/CDK5 signaling are also involved in the regulation of Aβ [114], and it is possible that if the treatment was longer, this effect would be detected.…”

“…Following the same line of investigation, Orejana et al [114] treated senescence-accelerated mouse-prone 8 (SAMP8, used as a model of aging, which displays many established pathological features of AD) with sildenafil (7.5 mg/kg, i.p., for 4 weeks) and showed that the mechanism of protection is through Aβ decrease, by pAkt/GSK3β /cathepsin B pathway and calpain/p25/CDK5/BACE1 pathway inhibition. pAkt inhibits GSK3β, which is an important activator of cathepsin B [115].…”

“…The work by Orejana et al [114] was perhaps one of the first studies to suggest and demonstrate that sildenafil modulates inflammatory cells in AD model. They showed that sildenafil decreased the GFAP, a marker of astrogliosis.…”

“…They showed that sildenafil decreased the GFAP, a marker of astrogliosis. However, Orejana et al [114] could not differentiate whether the reduction in GFAP levels resulted from less accumulation of Aβ or if it was a direct modulation of inflammatory events by sildenafil. A recent study using sildenafil in cultured astrocytes confirmed that sildenafil has a direct mechanism on neuroinflammation [116].…”