title: SET translocation is associated with increase in caspase cleaved amyloid precursor protein in CA1 of Alzheimer and Down syndrome patients.
abstract: Caspase cleaved amyloid precursor protein (APPcc) and SET are increased and mislocalized in the neuronal cytoplasm in Alzheimer Disease (AD) brains. Translocated SET to the cytoplasm can induce tau hyperphosphorylation. To elucidate the putative relationships between mislocalized APPcc and SET, we studied their level and distribution in the hippocampus of 5 controls, 3 Down syndrome and 10 Alzheimer patients. In Down syndrome and Alzheimer patients, APPcc and SET levels were increased in CA1 and the frequency of both localizations in the neuronal cytoplasm was high in CA1, and low in CA4. As the increase of APPcc is already present at early stages of AD, we overexpressed APPcc in CA1 and the dentate gyrus neurons of adult mice with a lentiviral construct. APPcc overexpression in CA1 and not in the dentate gyrus induced endogenous SET translocation and tau hyperphosphorylation. These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation.
authors.affiliation: INSERM UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Facchinetti
authors.affiliation: INSERM UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Dorard
authors.affiliation: ImagoSeine, Institut Jacques Monod, UMR 7592, CNRS and Université Paris Diderot, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Contremoulins
authors.affiliation: URA CEA CNRS 2210, Fontenay-aux-Roses, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gaillard
authors.affiliation: URA CEA CNRS 2210, Fontenay-aux-Roses, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.affiliation: Laboratoire de Neuropathologie Escourolle, Hôpital de la Salpêtrière, AP-HP, and Centre de Recherche de l'ICM (UPMC, INSERM UMR S 975, CNRS UMR 7225), Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Sazdovitch
authors.affiliation: EA 4064, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Guihenneuc-Jouyaux
authors.affiliation: URA CEA CNRS 2210, Fontenay-aux-Roses, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.affiliation: Laboratoire de Neuropathologie Escourolle, Hôpital de la Salpêtrière, AP-HP, and Centre de Recherche de l'ICM (UPMC, INSERM UMR S 975, CNRS UMR 7225), Paris, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.affiliation: INSERM UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Electronic address: bernadette.allinquant@inserm.fr.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Allinquant
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism*; D020169:Caspases / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism; D018450:Disease Progression; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056488:Histone Chaperones / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D014157:Transcription Factors / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C513473:SET protein, human; D014157:Transcription Factors; D016875:tau Proteins; D020169:Caspases
keywords: Alzheimer disease; Caspase cleaved APP; Down syndrome; Hippocampus; SET translocation; Tau hyperphosphorylation