Female Hippocampus Vulnerability to Environmental Stress, a Precipitating Factor in Tau Aggregation Pathology

Article type: Research Article

Authors: Sotiropoulos, Ioannis^{a; c; d; *} | Silva, Joana^{c; d} | Kimura, Tetsuya^{a; b} | Rodrigues, Ana Joao^{c; d} | Costa, Patricio^{c; d} | Almeida, Osborne F.X.^e | Sousa, Nuno^{c; d} | Takashima, Akihiko^{a; b}

Affiliations: [a] RIKEN Brain Science Institute, Laboratory for Alzheimer's Disease, Wako-shi, Saitama, Japan | [b] Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Ohbu, Japan | [c] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, Braga, Portugal | [d] ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal | [e] Max Planck Institute of Psychiatry, Munich, Germany

Correspondence: [*] Correspondence to: Ioannis Sotiropoulos, Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710 057 Braga, Portugal. Tel.: +351 253 604924; E-mail: [email protected].

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.

Keywords: Chaperones, hippocampus, memory, mice, stress, tau aggregates

DOI: 10.3233/JAD-140693

Journal: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 763-774, 2015