title: Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice.
abstract: Caspases have critical roles in Alzheimer's disease pathogenesis. Here we show that caspase-2 is required for the cognitive decline seen in human amyloid precursor protein transgenic mice (J20). The age-related changes in behaviour and dendritic spine density observed in these mice are absent when they lack caspase-2, in spite of similar levels of amyloid beta (Aβ) deposition and inflammation. A similar degree of protection is observed in cultured hippocampal neurons lacking caspase-2, which are immune to the synaptotoxic effects of Aβ. Our studies suggest that caspase-2 is a critical mediator in the activation of the RhoA/ROCK-II signalling pathway, leading to the collapse of dendritic spines. We propose that this is controlled by an inactive caspase-2/RhoA/ROCK-II complex localized in dendrites, which dissociates in the presence of Aβ, allowing for their activation and entry in the spine. These findings directly implicate caspase-2 as key driver of synaptic dysfunction in Alzheimer's disease and offer novel therapeutic targets.
authors.affiliation: Department of Pathology and Cell Biology and The Taub Institute for Research on Alzheimer's Disease and the Aging Brain v, Columbia University, New York, NY 10032, USA.
authors.forename: Julio
authors.initials: J
authors.lastname: Pozueta
authors.forename: Roger
authors.initials: R
authors.lastname: Lefort
authors.forename: Elena M
authors.initials: EM
authors.lastname: Ribe
authors.forename: Carol M
authors.initials: CM
authors.lastname: Troy
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Michael
authors.initials: M
authors.lastname: Shelanski
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology*; D015153:Blotting, Western; D053143:Caspase 2 / Q000172:deficiency / Q000378:metabolism*; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D008569:Memory Disorders / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D054460:rho-Associated Kinases; C090208:Casp2 protein, mouse; D053143:Caspase 2; D020742:rhoA GTP-Binding Protein