Tau Protein Phosphorylation in Diverse Brain Areas of Normal and CRH Deficient Mice: Up-Regulation by Stress

Abstract

Tau protein misfolding is a pathological mechanism, which plays a critical role in the etiopathogenesis of neurodegeneration. However, it is not entirely known what kind of stimuli can induce the misfolding. It is believed that physical and emotional stresses belong to such risk factors. Although the influence of stress on the onset and progression of Alzheimer's disease (AD) has already been proposed, the molecular links between stresses and AD are still unknown. We have therefore focused our attention on determination of the influence of acute immobilization stress (IMO) in normal mice and mice deficient in corticotropin-releasing hormone (CRH). Specifically, we have analyzed levels of hyperphosphorylated tau proteins, bearing the AD-specific phospho-epitopes (AT-8, pT181, and PHF-1), which are implicated in the pathogenesis of AD. We found that IMO induces transient hyperphosphorylation of tau proteins regardless of continuation of the stimulus. Concerning tau modifications, detailed analysis of the mouse brain revealed that neurons in different brain regions including frontal cortex, temporal cortex, hippocampal C1 and CA3 regions, dentate gyrus as well as nucleus basalis Meynert, and several brainstem nuclei such as locus coeruleus but also raphe nucleus and substantia nigra respond similarly to IMO. The strongest tau protein phosphorylation was observed after 30 min of IMO stress. Stress lasting for 120 min led either to the disappearance of tau hyperphosphorylation or to the induction of a second wave of hyperphosphorylation. Noteworthy is the magnitude of pathological phosphorylation of tau protein in CRH and glucocorticoids deficient mice, being much lower in comparison to that observed in wild-type animals, which suggests a critical role of CRH in the pathogenesis of AD. Thus, our results indicate that hyperphosphorylation of tau protein induced by stress may represent the pathogenic event upstream of tau protein misfolding, which leads to progression or eventually initiation of neurodegeneration. The data show that CRH plays an important role in stress induced hyperphosphorylation of tau protein, which might be either a direct effect of CRH innervations in the brain or an effect mediated via the hypothalamo-pituitary-adrenal axis.

Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain

“…, ; Filipcik et al . ). These data add to a conflicting set of data associating Crh with synaptotoxicity and AD and highlights a need for studies directly examining the interplay between Crh and AD.…”

Corticotropin-releasing factor receptor-dependent effects of repeated stress on tau phosphorylation, solubility, and aggregation

“…1) demonstrated no reliable variations in tau-P as a function of treatment. These brain regions are capable of displaying increments in tau-P in response to ostensibly more potent stressors (29,30). Whether their capacity to do so depends on the nature and/or intensity of stress, and whether CRFR signaling may be involved, remain to be determined.…”

The relationship between subcortical tau pathology and Alzheimer's disease

“…acute immobilization stress induces transient tau hyperphosphorylation in various brain regions including the LC, hippocampus and neocortex in C57B1/6 (wild-type) mice, but not in mice deficient in corticotropin-releasing hormone [22]. acute immobilization stress induces transient tau hyperphosphorylation in various brain regions including the LC, hippocampus and neocortex in C57B1/6 (wild-type) mice, but not in mice deficient in corticotropin-releasing hormone [22].…”