title: The transcription factor XBP1s restores hippocampal synaptic plasticity and memory by control of the Kalirin-7 pathway in Alzheimer model.
abstract: Neuronal network dysfunction and cognitive decline constitute the most prominent features of Alzheimer's disease (AD), although mechanisms causing such impairments are yet to be determined. Here we report that virus-mediated delivery of the active spliced transcription factor X-Box binding protein 1s (XBP1s) in the hippocampus rescued spine density, synaptic plasticity and memory function in a mouse model of AD. XBP1s transcriptionally activated Kalirin-7 (Kal7), a protein that controls synaptic plasticity. In addition, we found reduced levels of Kal7 in primary neurons exposed to Aβ oligomers, transgenic mouse models and human AD brains. Short hairpin RNA-mediated knockdown of Kal7 altered synaptic plasticity and memory formation in naive mice. Further, reduction of endogenous Kal7 compromised the beneficial effects of XBP1s in Alzheimer's model. Hence, our findings reveal that XBP1s is neuroprotective through a mechanism that engages Kal7 pathway with therapeutic implications in AD pathology.
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Sophia-Antipolis, Valbonne, France.
authors.forename: M
authors.initials: M
authors.lastname: Cissé
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Sophia-Antipolis, Valbonne, France.
authors.forename: E
authors.identifier: 0000-0002-1348-1507
authors.initials: E
authors.lastname: Duplan
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Sophia-Antipolis, Valbonne, France.
authors.forename: T
authors.initials: T
authors.lastname: Lorivel
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Sophia-Antipolis, Valbonne, France.
authors.forename: J
authors.initials: J
authors.lastname: Dunys
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Sophia-Antipolis, Valbonne, France.
authors.forename: C
authors.initials: C
authors.lastname: Bauer
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Sophia-Antipolis, Valbonne, France.
authors.forename: X
authors.initials: X
authors.lastname: Meckler
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Sophia-Antipolis, Valbonne, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Gerakis
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Sophia-Antipolis, Valbonne, France.
authors.forename: I
authors.initials: I
authors.lastname: Lauritzen
authors.affiliation: Université de Nice-Sophia-Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR7275, Sophia-Antipolis, Valbonne, France.
authors.forename: F
authors.initials: F
authors.lastname: Checler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C548820:KALRN protein, mouse; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C503866:KALRN protein, human; D017346:Protein Serine-Threonine Kinases