title: Caspase-2 cleavage of tau reversibly impairs memory.
abstract: In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.
authors.affiliation: N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, Minnesota, USA.|Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.|Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhao
authors.affiliation: N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, Minnesota, USA.|Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.|Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Kotilinek
authors.affiliation: N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, Minnesota, USA.|Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.|Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Smith
authors.affiliation: N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, Minnesota, USA.|Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.|Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Hlynialuk
authors.affiliation: N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, Minnesota, USA.|Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.|Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Zahs
authors.affiliation: N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, Minnesota, USA.|Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.|Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Ramsden
authors.affiliation: N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, Minnesota, USA.|Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.|Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA.|Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center, Minneapolis, Minnesota, USA.
authors.forename: James
authors.initials: J
authors.lastname: Cleary
authors.affiliation: N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, Minnesota, USA.|Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.|Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA.|Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center, Minneapolis, Minnesota, USA.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Ashe
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D015153:Blotting, Western; D053143:Caspase 2 / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism*; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008568:Memory; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D060172:Morpholinos; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009929:Organ Size; D017470:Receptors, Glutamate / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D060172:Morpholinos; D017470:Receptors, Glutamate; D016875:tau Proteins; C090208:Casp2 protein, mouse; D053143:Caspase 2; D020169:Caspases