title: Female hippocampus vulnerability to environmental stress, a precipitating factor in Tau aggregation pathology.
abstract: Tau-mediated neurodegeneration is a central event in Alzheimer's disease (AD) and other tauopathies. Consistent with suggestions that lifetime stress may be a clinically-relevant precipitant of AD pathology, we previously showed that stress triggers Tau hyperphosphorylation and accumulation; however, little is known about the etiopathogenic interaction of chronic stress with other AD risk factors, such as sex and aging. This study focused on how these various factors converge on the cellular mechanisms underlying Tau aggregation in the hippocampus of chronically stressed male and female (middle-aged and old) mice expressing the most commonly found disease-associated Tau mutation in humans, P301L-Tau. We report that environmental stress triggers memory impairments in female, but not male, P301L-Tau transgenic mice. Furthermore, stress elevates levels of caspase-3-truncated Tau and insoluble Tau aggregates exclusively in the female hippocampus while it also alters the expression of the molecular chaperones Hsp90, Hsp70, and Hsp105, thus favoring accumulation of Tau aggregates. Our findings provide new insights into the molecular mechanisms through which clinically-relevant precipitating factors contribute to the pathophysiology of AD. Our data point to the exquisite sensitivity of the female hippocampus to stress-triggered Tau pathology.
authors.affiliation: RIKEN Brain Science Institute, Laboratory for Alzheimer's Disease, Wako-shi, Saitama, Japan Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, Braga, Portugal ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Sotiropoulos
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, Braga, Portugal ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Silva
authors.affiliation: RIKEN Brain Science Institute, Laboratory for Alzheimer's Disease, Wako-shi, Saitama, Japan Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Ohbu, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, Braga, Portugal ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Ana Joao
authors.initials: AJ
authors.lastname: Rodrigues
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, Braga, Portugal ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Patricio
authors.initials: P
authors.lastname: Costa
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Osborne F X
authors.initials: OF
authors.lastname: Almeida
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, Braga, Portugal ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Sousa
authors.affiliation: RIKEN Brain Science Institute, Laboratory for Alzheimer's Disease, Wako-shi, Saitama, Japan Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Ohbu, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takashima
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D015985:Precipitating Factors; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D053148:Caspase 3
keywords: Chaperones; hippocampus; memory; mice; stress; tau aggregates