title: Specific calpain inhibition by calpastatin prevents tauopathy and neurodegeneration and restores normal lifespan in tau P301L mice.
abstract: Tau pathogenicity in Alzheimer's disease and other tauopathies is thought to involve the generation of hyperphosphorylated, truncated, and oligomeric tau species with enhanced neurotoxicity, although the generative mechanisms and the implications for disease therapy are not well understood. Here, we report a striking rescue from mutant tau toxicity in the JNPL3 mouse model of tauopathy. We show that pathological activation of calpains gives rise to a range of potentially toxic forms of tau, directly, and by activating cdk5. Calpain overactivation in brains of these mice is accelerated as a result of the marked depletion of the endogenous calpain inhibitor, calpastatin. When levels of this inhibitor are restored in neurons of JNPL3 mice by overexpressing calpastatin, tauopathy is prevented, including calpain-mediated breakdown of cytoskeletal proteins, cdk5 activation, tau hyperphosphorylation, formation of potentially neurotoxic tau fragments by either calpain or caspase-3, and tau oligomerization. Calpastatin overexpression also prevents loss of motor axons, delays disease onset, and extends survival of JNPL3 mice by 3 months to within the range of normal lifespan. Our findings support the therapeutic promise of highly specific calpain inhibition in the treatment of tauopathies and other neurodegenerative states.
authors.affiliation: Center for Dementia Research and Departments of Psychiatry and rao@nki.rfmh.org.
authors.forename: Mala V
authors.initials: MV
authors.lastname: Rao
authors.affiliation: Center for Dementia Research and.
authors.forename: Mary Kate
authors.initials: MK
authors.lastname: McBrayer
authors.affiliation: Center for Dementia Research and.
authors.forename: Jabbar
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Center for Dementia Research and.
authors.forename: Asok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Division of Neurochemistry, Nathan Kline Institute, Orangeburg, New York 10962.
authors.forename: Audrey
authors.initials: A
authors.lastname: Hashim
authors.affiliation: Division of Neurochemistry, Nathan Kline Institute, Orangeburg, New York 10962.
authors.forename: Henry
authors.initials: H
authors.lastname: Sershen
authors.affiliation: Center for Dementia Research and.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Stavrides
authors.affiliation: Center for Dementia Research and Departments of Psychiatry and.
authors.forename: Masuo
authors.initials: M
authors.lastname: Ohno
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
authors.affiliation: Center for Dementia Research and Departments of Psychiatry and Cell Biology, New York University Langone Medical Center, New York, New York 10016, and.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002135:Calcium-Binding Proteins / Q000008:administration & dosage*; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage; D005260:Female; D008136:Longevity / Q000187:drug effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D015996:Survival Rate; D024801:Tauopathies / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D016896:Treatment Outcome; D016875:tau Proteins / Q000187:drug effects / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; C054369:MAPT protein, human; D016875:tau Proteins; C033668:calpastatin; D002154:Calpain
keywords: ambulatory movements; calcium; fractionation; insoluble extracts; nesting behavior