Abstract
Studies have indicated that early-life or early-onset depression is associated with a 2- to 4-fold increased risk of developing Alzheimers disease (AD). In AD, aggregation of an abnormally phosphorylated form of the tau protein may be a key pathological event. Tau is known to play a major role in promoting microtubule assembly and stabilization, and in maintaining the normal morphology of neurons. Several studies have reported that stress may induce tau phosphorylation. The main aim of the present study was to investigate possible alterations in the tau protein in the hippocampus and frontal cortex of 32 male Sprague-Dawley rats exposed to chronic unpredictable mild stress (CUMS) and then re-exposed to CUMS to mimic depression and the recurrence of depression, respectively, in humans. We evaluated the effects of CUMS, fluoxetine, and CUMS re-exposure on tau and phospho-tau. Our results showed that a single exposure to CUMS caused a significant reduction in sucrose preference, indicating a state of anhedonia. The change in behavior was accompanied by specific alterations in phospho-tau protein levels, but fluoxetine treatment reversed the CUMS-induced impairments. Moreover, changes in sucrose preference and phospho-tau were more pronounced in rats re-exposed to CUMS than in those subjected to a single exposure. Our results suggest that changes in tau phosphorylation may contribute to the link between depression and AD.
Highlights
Previous studies have shown an association between depression and dementia, and it has been suggested that lifetime depression is associated with a 2- to 4-fold increased risk of developing Alzheimer’s disease (AD) [14]
The present study revealed elevation of the levels of phosphorylated tau in the hippocampus and frontal cortex of depressive animals, which may indicate a link between depression and AD
In AD brains, tau moves from the axons to the somatodendritic compartment of neurons, where it forms hyperphosphorylated, filamentous aggregates described as neurofibrillary tangles
Summary
Previous studies have shown an association between depression and dementia, and it has been suggested that lifetime depression is associated with a 2- to 4-fold increased risk of developing Alzheimer’s disease (AD) [14]. A cross-sectional (case-controlled) study suggested that a history of depression, even 25 years prior to AD onset, was significantly associated with an almost 2-fold increase in the likelihood of developing AD, and that depression symptoms within the year before the onset of AD were associated with an almost 5-fold increased risk [4]. Growing evidence indicates that the cytoskeleton, a structural system including microtubules and microtubuleassociated proteins (MAPs), may play an important role in stress-induced impairments of neuronal structural plasticity [10]. Developmental and functional regulation of phosphorylation modulates the function of tau proteins in controlling microtubule dynamics during normal neurite outgrowth and maturation. Accumulating evidence suggests that hyperphosphorylated tau sequesters normal MAPs and disrupts
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