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dc.contributor.authorTonegawa, Susumu
dc.contributor.authorArsenault, Dany
dc.contributor.authorDal-Pan, Alexandre
dc.contributor.authorTremblay, Cyntia
dc.contributor.authorBennett, David A.
dc.contributor.authorGuitton, Matthieu J.
dc.contributor.authorDe Koninck, Yves
dc.contributor.authorCalon, Frederic
dc.date.accessioned2014-02-28T14:11:40Z
dc.date.available2014-02-28T14:11:40Z
dc.date.issued2013-06
dc.date.submitted2013-05
dc.identifier.issn0270-6474
dc.identifier.issn1529-2401
dc.identifier.urihttp://hdl.handle.net/1721.1/85179
dc.description.abstractDefects in p21-activated kinase (PAK) are suspected to play a role in cognitive symptoms of Alzheimer's disease (AD). Dysfunction in PAK leads to cofilin activation, drebrin displacement from its actin-binding site, actin depolymerization/severing, and, ultimately, defects in spine dynamics and cognitive impairment in mice. To determine the role of PAK in AD, we first quantified PAK by immunoblotting in homogenates from the parietal neocortex of subjects with a clinical diagnosis of no cognitive impairment (n = 12), mild cognitive impairment (n = 12), or AD (n = 12). A loss of total PAK, detected in the cortex of AD patients (−39% versus controls), was correlated with cognitive impairment (r[superscript 2] = 0.148, p = 0.027) and deposition of total and phosphorylated tau (r[superscript 2] = 0.235 and r[superscript 2] = 0.206, respectively), but not with Aβ42 (r[superscript 2] = 0.056). Accordingly, we found a decrease of total PAK in the cortex of 12- and 20-month-old 3xTg-AD mice, an animal model of AD-like Aβ and tau neuropathologies. To determine whether PAK dysfunction aggravates AD phenotype, 3xTg-AD mice were crossed with dominant-negative PAK mice. PAK inactivation led to obliteration of social recognition in old 3xTg-AD mice, which was associated with a decrease in cortical drebrin (−25%), but without enhancement of Aβ/tau pathology or any clear electrophysiological signature. Overall, our data suggest that PAK decrease is a consequence of AD neuropathology and that therapeutic activation of PAK may exert symptomatic benefits on high brain function.en_US
dc.language.isoen_US
dc.publisherSociety for Neuroscienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1523/JNEUROSCI.1501-13.2013en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourceSociety for Neuroscienceen_US
dc.titlePAK Inactivation Impairs Social Recognition in 3xTg-AD Mice without Increasing Brain Deposition of Tau and Aβen_US
dc.typeArticleen_US
dc.identifier.citationArsenault, D. et al. “PAK Inactivation Impairs Social Recognition in 3xTg-AD Mice without Increasing Brain Deposition of Tau and A.” Journal of Neuroscience 33.26 (2013): 10729–10740.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorTonegawa, Susumuen_US
dc.relation.journalJournal of Neuroscienceen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsArsenault, D.; Dal-Pan, A.; Tremblay, C.; Bennett, D. A.; Guitton, M. J.; De Koninck, Y.; Tonegawa, S.; Calon, F.en_US
dc.identifier.orcidhttps://orcid.org/0000-0003-2839-8228
mit.licensePUBLISHER_POLICYen_US
mit.metadata.statusComplete


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