title: Phosphorylated tau potentiates Aβ-induced mitochondrial damage in mature neurons.
abstract: Tau phosphorylated at the PHF-1 epitope (S396/S404) is likely involved in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which tau phosphorylated at these sites negatively impacts neuronal functions are still under scrutiny. Previously, we showed that expression of tau truncated at D421 enhances mitochondrial dysfunction induced by Aβ in cortical neurons. To extend these findings, we expressed tau pseudo-phosphorylated at S396/404 (T42EC) in mature and young cortical neurons and evaluated different aspects of mitochondrial function in response to Aβ. Expression of T42EC did not induce significant changes in mitochondrial morphology, mitochondrial length, or mitochondrial transport, compared to GFP and full-length tau. However, T42EC expression enhanced Aβ-induced mitochondrial membrane potential loss and increased superoxide levels compared to what was observed in mature neurons expressing full-length tau. The same effect was observed in mature neurons that expressed both pseudo-phosphorylated and truncated tau when they were treated with Aβ. Interestingly, the mitochondrial failure induced by Aβ in mature neurons that expressed T42EC, was not observed in young neurons expressing T42EC. These novel findings suggest that phosphorylated tau (PHF-1 epitope) enhances Aβ-induced mitochondrial injury, which contributes to neuronal dysfunction and to the pathogenesis of AD.
authors.affiliation: Centro de Investigación Biomédica, Universidad Autónoma de Chile, Santiago, Chile; Laboratorio de Neurociencias, Departamento de Neurología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile. Electronic address: rodrigo.quintanilla@uautonoma.cl.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Quintanilla
authors.affiliation: Laboratorio de Neurociencias, Departamento de Neurología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Rommy
authors.initials: R
authors.lastname: von Bernhardi
authors.affiliation: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Godoy
authors.affiliation: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Gail V W
authors.initials: GV
authors.lastname: Johnson
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D049452:Green Fluorescent Proteins / Q000235:genetics; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects*; D010766:Phosphorylation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D013481:Superoxides / Q000378:metabolism; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D016875:tau Proteins; D013481:Superoxides; D049452:Green Fluorescent Proteins
keywords: Alzheimer's disease; Mitochondria; Neuronal dysfunction; PHF-1; Tau