title: Strain-Specific Altered Regulatory Response of Rab7a and Tau in Creutzfeldt-Jakob Disease and Alzheimer's Disease.
abstract: There is an increasing demand for the understanding of pathophysiology on neurodegeneration diseases at early stages. Changes in endocytic machinery and the cytoskeleton-associated response are the first alterations observed in Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease AD brain. In this study, we performed a targeted search for endocytic pathway proteins in the different regions of the brain. We found late endosome marker Rab7a which was significantly upregulated in the frontal cortex region in the rapid progressive CJD form (MM1) and rapid progressive AD (rpAD) forms. However, Rab9 expression was significantly downregulated only in CJD-MM1 brain frontal cortex region. In the cerebellum, Rab7a expression showed significant upregulation in both subtype MM1 and VV2 CJD forms, in contrast to Rab9 which showed significant downregulation in both subtype MM1 and VV2 CJD forms at terminal stage of the disease. To check regulatory response at pre-symptomatic stage of the disease, we checked the regulatory interactive response of Rab7a, Rab9, and known biomarkers PrPCand tau forms in frontal cortex at pre-symptomatic stage of the disease in tg340 mice expressing about fourfold of human PrP-M129 with PrP-null background that had been inoculated with human sCJD MM1 brain tissue homogenates (sCJD MM1 mice). In addition, we analyzed 5XFAD mice, exhibiting five mutations in the APP and presenilin genes related to familial Alzheimer's disease (FAD), to validate specific regulatory response of Rab7a, Rab9, tau, and phosphorylated form of tau by immunostaining 5XFAD mice in comparison with the wild-type age-matched mice brain. The cortical region of 5XFAD mice brain showed accumulated form of Rab7a in puncta that co-label for p-Tau, indicating colocalization by using confocal laser-scanning microscopy and was confirmed by using reverse co-immunoprecipitation. Furthermore, synthetic RNA (siRNA) against the Rab7a gene decreased expression of Rab7a protein, in cortical primary neuronal cultures of PrPCwild type. This depleted expression of Rab7a led to the increased accumulation of PrPCin Rab9-positive endosomal compartments and consequently an increased co-localization between PrPC/Rab9; however, total tau level decreased. Interestingly, siRNA against tau gene in cortical primary neuronal cultures of PrPCwild-type mice showed enhanced Rab7a and Rab9 expression and increase formation of dendritic spines. The work described highlighted the selective involvement of late endosomal compartment marker Rab7a in CJD, slow and rapid progressive forms of AD pathogenesis.
authors.affiliation: Department of Neurology, Clinical Dementia Center and DZNE, University Medical Centre Goettingen, 37075, Goettingen, Germany. sz_awaan@yahoo.com.
authors.forename: Saima
authors.initials: S
authors.lastname: Zafar
authors.affiliation: Department of Neurology, Clinical Dementia Center and DZNE, University Medical Centre Goettingen, 37075, Goettingen, Germany.
authors.forename: Neelam
authors.initials: N
authors.lastname: Younas
authors.affiliation: Department of Neurology, Clinical Dementia Center and DZNE, University Medical Centre Goettingen, 37075, Goettingen, Germany.
authors.forename: Susana
authors.initials: S
authors.lastname: Correia
authors.affiliation: Department of Neurology, Clinical Dementia Center and DZNE, University Medical Centre Goettingen, 37075, Goettingen, Germany.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Shafiq
authors.affiliation: Department of Neurology, Clinical Dementia Center and DZNE, University Medical Centre Goettingen, 37075, Goettingen, Germany.
authors.forename: Waqas
authors.initials: W
authors.lastname: Tahir
authors.affiliation: Department of Neurology, Clinical Dementia Center and DZNE, University Medical Centre Goettingen, 37075, Goettingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmitz
authors.affiliation: Institute of Neuropathology, IDIBELL-University Hospital Bellvitge, University of Barcelona, Hospitalet de Llobregat, Spain.|CIBERNED (Network center for biomedical research of neurodegenerative diseases), Institute Carlos III, Ministry of Health, Madrid, Spain.
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: UMR INRA ENVT 1225, Interactions Hôtes Agents Pathogènes, Ecole Nationale Vétérinaire de Toulouse, 23 Chemin des Capelles 31076, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Andréoletti
authors.affiliation: Department of Neurology, Clinical Dementia Center and DZNE, University Medical Centre Goettingen, 37075, Goettingen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Zerr
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004705:Endocytosis / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D013045:Species Specificity; D020691:rab GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D000090802:rab7 GTP-Binding Proteins; D016875:tau Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C054369:MAPT protein, human; D000090802:rab7 GTP-Binding Proteins; D016875:tau Proteins; D020691:rab GTP-Binding Proteins
keywords: 5XFAD mice; Alzheimer’s disease; CJD; Cerebellum; Frontal cortex; Interacting protein; Rab7a; Rab9; Rapid progressive AD; Tau; siRNA