title: Caspase-3-dependent cleavage of Akt modulates tau phosphorylation via GSK3β kinase: implications for Alzheimer's disease.
abstract: The pathological hallmark of Alzheimer's disease (AD) is accumulation of misfolded amyloid-β peptides and hyperphosphorylated tau protein in the brain. Increasing evidence suggests that serine-aspartyl proteases-caspases are activated in the AD brain. Previous studies identified a caspase-3 cleavage site within the amyloid-β precursor protein, and a caspase-3 cleavage of tau as the mechanisms involved in the development of Aβ and tau neuropathology, respectively. However, the potential role that caspase-3 could have on tau metabolism remains unknown. In the current studies, we provide experimental evidence that caspase-3 directly and specifically regulates tau phosphorylation, and demonstrate that this effect is mediated by the GSK3β kinase pathway via a caspase-3-dependent cleavage of the protein kinase B (also known as Akt). In addition, we confirm these results in vivo by using a transgenic mouse model of AD. Collectively, our findings demonstrate a new role for caspase-3 in the neurobiology of tau, and suggest that therapeutic strategies aimed at inhibiting this protease-dependent cleavage of Akt may prove beneficial in preventing tau hyperphosphorylation and subsequent neuropathology in AD and related tauopathies.
authors.affiliation: Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chu
authors.affiliation: Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lauretti
authors.affiliation: Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D024801:Tauopathies / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D051058:Oncogene Protein v-akt; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3