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Free keywords:
chronic stress, dendritic atrophy, mitochondria, prefrontal cortex, Tau knock-out
Abstract:
Tau protein in dendrites and synapses has been recently implicated in
synaptic degeneration and neuronal malfunction. Chronic stress, a
well-known inducer of neuronal/synaptic atrophy, triggers
hyperphosphorylation of Tau protein and cognitive deficits. However, the
cause-effect relationship between these events remains to be
established. To test the involvement of Tau in stress-induced
impairments of cognition, we investigated the impact of stress on
cognitive behavior, neuronal structure, and the synaptic proteome in the
prefrontal cortex (PFC) of Tau knock-out (Tau-KO) and wild-type (WT)
mice. Whereas exposure to chronic stress resulted in atrophy of apical
dendrites and spine loss in PFC neurons as well as significant
impairments in working memory in WT mice, such changes were absent in
Tau-KO animals. Quantitative proteomic analysis of PFC synaptosomal
fractions, combined with transmission electron microscopy analysis,
suggested a prominent role for mitochondria in the regulation of the
effects of stress. Specifically, chronically stressed animals exhibit
Tau-dependent alterations in the levels of proteins involved in
mitochondrial transport and oxidative phosphorylation as well as in the
synaptic localization of mitochondria in PFC. These findings provide
evidence for a causal role of Tau in mediating stress-elicited neuronal
atrophy and cognitive impairment and indicate that Tau may exert its
effects through synaptic mitochondria.
