Exaggerated phosphorylation of brain tau protein in CRH KO mice exposed to repeated immobilization stress

Abstract

Neuroendocrine and behavioral stress responses are orchestrated by corticotropin-releasing hormone (CRH) and norepinephrine (NE) synthesizing neurons. Recent findings indicate that stress may promote development of neurofibrillary pathology in Alzheimer's disease. Therefore, we investigated relationships among stress, tau protein phosphorylation, and brain NE using wild-type (WT) and CRH-knockout (CRH KO) mice. We assessed expression of phosphorylated tau (p-tau) at the PHF-1 epitope and NE concentrations in the locus coeruleus (LC), A1/C1 and A2/C2 catecholaminergic cell groups, hippocampus, amygdala, nucleus basalis magnocellularis, and frontal cortex of unstressed, singly stressed or repeatedly stressed mice. Moreover, gene expression and protein levels of tyrosine hydroxylase (TH) and CRH receptor mRNA were determined in the LC. Plasma corticosterone levels were also measured. Exposure to a single stress increases tau phosphorylation throughout the brain in WT mice when compared to singly stressed CRH KO animals. In contrast, repeatedly stressed CRH KO mice showed exaggerated tau phosphorylation relative to WT controls. We also observed differences in extent of tau phosphorylation between investigated structures, e.g. the LC and hippocampus. Moreover, CRH deficiency leads to different responses to stress in gene expression of TH, NE concentrations, CRH receptor mRNA, and plasma corticosterone levels. Our data indicate that CRH effects on tau phosphorylation are dependent on whether stress is single or repeated, and differs between brain regions. Our findings indicate that CRH attenuates mechanisms responsible for development of stress-induced tau neuropathology, particularly in conditions of chronic stress. However, the involvement of central catecholaminergic neurons in these mechanisms remains unclear and is in need of further investigation.

Neuroprotection of Tropical Fruit Juice Mixture via the Reduction of iNOS Expression and CRH Level in β‐Amyloid‐Induced Rats Model of Alzheimer’s Disease

“…In a transgenic mouse model of AD, chronic stress can induce Tau pathology, neurodegeneration, and learning impairment, which can be blocked by CRH receptor 1 antagonists and enhanced by CRH overexpression [56]. Previous studies have demonstrated that Crf mutant animals showed a reduction in both Aβ-and Tau-related pathologies [63,64]. Moreover, mutations in CRH receptor 1 have been proved to reduce Tau hyperphosphorylation and Aβ deposition in response to stress [65][66][67].…”

Down but Not Out: The Consequences of Pretangle Tau in the Locus Coeruleus

“…Similarly, cognitive performance in amnestic MCI and AD patients is negatively correlated with disruption of mitochondrial and cellular stress proteins in LC neurons, suggesting that early cellular stress in LC neurons may be contributing to AD progression [ 25 ]. Furthermore, the LC is a critical mediator of the physiologic stress response, and chronic stress increases tau hyperphosphorylation in the LC of mice [ 51 ]. Taken together, LC neurons appear to be susceptible to both cellular and physiologic stressors.…”

“…While studies show the presence of pretangle tau in the LC in young individuals, there is no way to determine whether these individuals would have eventually developed AD. Other factors (repeated concussions, stress, and heavy drug use) also increase hyperphosphorylated tau in the LC [ 46 , 51 , 55 , 70 ] and could trigger the appearance of aberrant tau. The only attempt to examine the spread of tau pathology from the LC experimentally delivered puzzling results.…”

Targeting psychologic stress signaling pathways in Alzheimer’s disease

“…Multiple stress paradigms have been able to increase tau phosphorylation in mice [53–60] (Table 4) and it was shown that a CRH KO mouse model did not show the stress induced increases in hyperphosphorylated tau that were seen in WT mice [57]. …”