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Chaperones, hippocampus, memory, mice, stress, tau aggregates
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.
