title: Fibrillar Amyloid-β Accumulation Triggers an Inflammatory Mechanism Leading to Hyperphosphorylation of the Carboxyl-Terminal End of Tau Polypeptide in the Hippocampal Formation of the 3×Tg-AD Transgenic Mouse.
abstract: Alzheimer's disease (AD) is a degenerative and irreversible disorder whose progressiveness is dependent on age. It is histopathologically characterized by the massive accumulation of insoluble forms of tau and amyloid-β (Aβ) asneurofibrillary tangles and neuritic plaques, respectively. Many studies have documented that these two polypeptides suffer several posttranslational modifications employing postmortem tissue sections from brains of patients with AD. In order to elucidate the molecular mechanisms underlying the posttranslational modifications of key players in this disease, including Aβ and tau, several transgenic mouse models have been developed. One of these models is the 3×Tg-AD transgenic mouse, carrying three transgenes encoding APPSWE, S1M146V, and TauP301L proteins. To further characterize this transgenicmouse, we determined the accumulation of fibrillar Aβ as a function of age in relation to the hyperphosphorylation patterns of TauP301L at both its N- and C-terminus in the hippocampal formation by immunofluorescence and confocal microscopy. Moreover, we searched for the expression of activated protein kinases and mediators of inflammation by western blot of wholeprotein extracts from hippocampal tissue sections since 3 to 28 months as well. Our results indicate that the presence of fibrillar Aβ deposits correlates with a significant activation of astrocytes and microglia in subiculum and CA1 regions of hippocampus. Accordingly, we also observed a significant increase in the expression of TNF-α associated to neuritic plaques and glial cells. Importantly, there is an overexpression of the stress activated protein kinases SAPK/JNK and Cdk-5 in pyramidal neurons, which might phosphorylate several residues at the C-terminus of TauP301L. Therefore, the accumulation of Aβ oligomers results in an inflammatory environment that upregulates kinases involved in hyperphosphorylation of TauP301L polypeptide.
authors.affiliation: Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Col. San Pedro Zacatenco, Ciudad de México, México.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Ontiveros-Torres
authors.affiliation: Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Col. San Pedro Zacatenco, Ciudad de México, México.
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Labra-Barrios
authors.affiliation: Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Juriquilla, Querétaro, Qro., México.
authors.forename: Sofía
authors.initials: S
authors.lastname: Díaz-Cintra
authors.affiliation: Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Juriquilla, Querétaro, Qro., México.
authors.forename: Azucena Ruth
authors.initials: AR
authors.lastname: Aguilar-Vázquez
authors.affiliation: Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Col. San Pedro Zacatenco, Ciudad de México, México.
authors.forename: Samadhi
authors.initials: S
authors.lastname: Moreno-Campuzano
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Col. San Pedro Zacatenco, Ciudad de México, México.|Present address: Departamento de Fisiología, Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Durango, Dgo., México.
authors.forename: Paola
authors.initials: P
authors.lastname: Flores-Rodríguez
authors.affiliation: Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Campus Zacatenco, Ciudad de México, México.
authors.forename: Claudia
authors.initials: C
authors.lastname: Luna-Herrera
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Col. San Pedro Zacatenco, Ciudad de México, México.
authors.forename: Raúl
authors.initials: R
authors.lastname: Mena
authors.affiliation: College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA.
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Col. San Pedro Zacatenco, Ciudad de México, México.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Florán-Garduño
authors.affiliation: Banco Nacional de Cerebros, Laboratorio Nacional de Servicios Experimentales, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Col. San Pedro Zacatenco, Ciudad de México, México.
authors.forename: José
authors.initials: J
authors.lastname: Luna-Muñoz
authors.affiliation: Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Col. San Pedro Zacatenco, Ciudad de México, México.
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Luna-Arias
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology* / Q000473:pathology; D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009457:Neuroglia / Q000276:immunology / Q000473:pathology; D010766:Phosphorylation / Q000276:immunology; D058225:Plaque, Amyloid / Q000276:immunology / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D017966:Pyramidal Cells / Q000276:immunology / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins
keywords: 3×Tg-AD transgenic mouse; Amyloid-β; TauP301L; hippocampus; inflammation