title: Tauopathy contributes to synaptic and cognitive deficits in a murine model for Alzheimer's disease.
abstract: Tau alterations are now considered an executor of neuronal demise and cognitive dysfunction in Alzheimer's disease (AD). Mouse models combining amyloidosis and tauopathy and their parental counterparts are important tools to further investigate the interplay of abnormal amyloid-β (Aβ) and Tau species in pathogenesis, synaptic and neuronal dysfunction, and cognitive decline. Here, we crossed APP/PS1 mice with 5 early-onset familial AD mutations (5xFAD) and TauP301S (PS19) transgenic mice, denoted F(+)/T(+) mice, and phenotypically compared them to their respective parental strains, denoted F(+)/T(-) and F(-)/T(+) respectively, as controls. We found dramatically aggravated tauopathy (~10-fold) in F(+)/T(+) mice compared to the parental F(-)/T(+) mice. In contrast, amyloidosis was unaltered compared to the parental F(+)/T(-) mice. Tauopathy was invariably and very robustly aggravated in hippocampal and cortical brain regions. Most important, F(+)/T(+) displayed aggravated cognitive deficits in a hippocampus-dependent spatial navigation task, compared to the parental F(+)/T(-) strain, while parental F(-)/T(+) mice did not display cognitive impairment. Basal synaptic transmission was impaired in F(+)/T(+) mice compared to nontransgenic mice and the parental strains (≥40%). Finally, F(+)/T(+) mice displayed a significant hippocampal atrophy (~20%) compared to nontransgenic mice, in contrast to the parental strains. Our data indicate for the first time that pathological Aβ species (or APP/PS1) induced changes in Tau contribute to cognitive deficits correlating with synaptic deficits and hippocampal atrophy in an AD model. Our data lend support to the amyloid cascade hypothesis with a role of pathological Aβ species as initiator and pathological Tau species as executor.
authors.affiliation: Alzheimer Dementia Group and.
authors.forename: Ilie-Cosmin
authors.initials: IC
authors.lastname: Stancu
authors.affiliation: Department of Neurosciences, University of Mons, Mons, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Ris
authors.affiliation: Alzheimer Dementia Group and.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vasconcelos
authors.affiliation: Alzheimer Dementia Group and.
authors.forename: Claudia
authors.initials: C
authors.lastname: Marinangeli
authors.affiliation: Alzheimer Dementia Group and.
authors.forename: Léonie
authors.initials: L
authors.lastname: Goeminne
authors.affiliation: Alzheimer Dementia Group and.
authors.forename: Vincent
authors.initials: V
authors.lastname: Laporte
authors.affiliation: Alzheimer Dementia Group and.
authors.forename: Laetitia E
authors.initials: LE
authors.lastname: Haylani
authors.affiliation: Alzheimer Dementia Group and.
authors.forename: Julien
authors.initials: J
authors.lastname: Couturier
authors.affiliation: Department of Cell Physiology, Institute of Neuroscience, Catholic University of Louvain, Brussels, Belgium; and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Schakman
authors.affiliation: Department of Cell Physiology, Institute of Neuroscience, Catholic University of Louvain, Brussels, Belgium; and.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gailly
authors.affiliation: Alzheimer Dementia Group and.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pierrot
authors.affiliation: Alzheimer Dementia Group and.
authors.forename: Pascal
authors.initials: P
authors.lastname: Kienlen-Campard
authors.affiliation: Alzheimer Dementia Group and.
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Octave
authors.affiliation: Alzheimer Dementia Group and ilse.dewachter@uclouvain.be.
authors.forename: Ilse
authors.initials: I
authors.lastname: Dewachter
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001284:Atrophy / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics; D009435:Synaptic Transmission; D024801:Tauopathies / Q000150:complications* / Q000473:pathology; D016875:tau Proteins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D016875:tau Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3
keywords: GSK3; amyloid plaques; hippocampal atrophy; neurofibrillary tangles; synaptic transmission