title: 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.
authors: Department of Pharmacology, School of Pharmacy, University of Navarra, Spain.
authors: Lourdes
authors: L
authors: Orejana
authors: Department of Pharmacology, School of Pharmacy, University of Navarra, Spain.
authors: Lucía
authors: L
authors: Barros-Miñones
authors: Department of Medical Sciences, School of Medicine, University of Castilla-La Mancha and Regional Centre for Biomedical Research, Albacete, Spain.
authors: Joaquin
authors: J
authors: Jordan
authors: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer Disease Research Center, Stockholm, Sweden.
authors: Angel
authors: A
authors: Cedazo-Minguez
authors: Department of Pharmacology, School of Pharmacy, University of Navarra, Spain.
authors: Rosa M
authors: RM
authors: Tordera
authors: Department of Pharmacology, School of Pharmacy, University of Navarra, Spain.
authors: Norberto
authors: N
authors: Aguirre
authors: Department of Pharmacology, School of Pharmacy, University of Navarra, Spain. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer Disease Research Center, Stockholm, Sweden.
authors: Elena
authors: E
authors: Puerta
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism*; D003072:Cognition Disorders / Q000188:drug therapy; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D038341:Glycogen Synthase Kinases / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D023421:Models, Animal; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D012333:RNA, Messenger; D013449:Sulfonamides; D000068677:Sildenafil Citrate; D038341:Glycogen Synthase Kinases; D051360:Cyclin-Dependent Kinase 5; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D002154:Calpain; D002401:Cathepsin B; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat
keywords: Amyloid-β; BACE1; Cathepsin B; SAMP8; Sildenafil.