title: The novel calpain inhibitor A-705253 prevents stress-induced tau hyperphosphorylation in vitro and in vivo.
abstract: Calcium-mediated pathologic activation of the cysteine protease calpain has been linked to neurodegenerative disorders such as Alzheimer's disease (AD) through the cleavage of proteolytic substrates that negatively affect neuronal function. Hyperphosphorylation of the microtubule-associated protein tau and the subsequent aggregation of tau filaments resulting in the intracellular formation of neurofibrillary tangles are recognized as key etiological factors in AD pathology. Cyclin-dependent kinase 5 (Cdk5), a major kinase responsible for tau hyperphosphorylation in the AD brain, becomes hyperactivated through calpain-mediated cleavage-conversion of the Cdk5 regulatory protein p35 to p25. In the present study, we examined the effects of the novel small-molecule calpain inhibitor A-705253 in acute models of tau hyperphosphorylation in vitro and in vivo. In hippocampal slices in vitro, lowering medium temperature to 33 °C increased tau phosphorylation in which incubation with A-705253 blocked low temperature-induced tau phosphorylation as measured by Western blot analysis. Pentobarbital-induced hypothermia or acute systemic LPS treatment in normal mice increased tau phosphorylation in hippocampal CA3 mossy fibers, as measured by immunohistochemistry, whereas acute A-705253 pretreatment prevented the stress-induced tau hyperphosphorylation in both models. In support of a Cdk5-mediated mechanism, A-705253 administered for two weeks in the drinking water of six month-old prepathogenic 3x Tg-AD mice resulted in decreased expression of the calpain proteolytic p25 fragment. Taken together, results of these studies suggest that calpain inhibition has potential utility in reducing tau hyperphosphorylation and may represent a novel disease-modifying approach in the treatment of AD.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Rd., IL 60064, USA.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Nikkel
authors.forename: Brenda
authors.initials: B
authors.lastname: Martino
authors.forename: Stella
authors.initials: S
authors.lastname: Markosyan
authors.forename: Jill-Desiree
authors.initials: JD
authors.lastname: Brederson
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Medeiros
authors.forename: Achim
authors.initials: A
authors.lastname: Moeller
authors.forename: Robert S
authors.initials: RS
authors.lastname: Bitner
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003080:Cold Temperature / Q000009:adverse effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C500488:A-705253; D001549:Benzamides; D015853:Cysteine Proteinase Inhibitors; D010446:Peptide Fragments; D016875:tau Proteins; D002154:Calpain