Corticotropin-Releasing Factor Receptors Differentially Regulate Stress-Induced Tau Phosphorylation

Laboratory of Neuronal Structure and Function, Salk Institute, لا هویا, California, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2007; 27(24):6552-62. DOI: 10.1523/JNEUROSCI.5173-06.2007
Source: PubMed


Hyperphosphorylation of the microtubule-associated protein tau is a key event in the development of Alzheimer's disease (AD) neuropathology. Acute stress can induce hippocampal tau phosphorylation (tau-P) in rodents, but the mechanisms and pathogenic relevance of this response are unclear. Here, we find that hippocampal tau-P elicited by an acute emotional stressor, restraint, was not affected by preventing the stress-induced rise in glucocorticoids but was blocked by genetic or pharmacologic disruption of signaling through the type 1 corticotropin-releasing factor receptor (CRFR1). Conversely, these responses were exaggerated in CRFR2-deficient mice. Parallel CRFR dependence was seen in the stress-induced activation of specific tau kinases. Repeated stress exposure elicited cumulative effects on tau-P and its sequestration in an insoluble, and potentially pathogenic, form. These findings support differential regulatory roles for CRFRs in an AD-relevant form of neuronal plasticity and may link datasets documenting alterations in the CRF signaling system in AD and implicating chronic stress as a risk factor in age-related neurological disorders.

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Available from: Paul E Sawchenko, Feb 01, 2016
    • "Even though it has been suggested that stress represents a risk factor for development of AD [116], the role of stress in the pathogenesis of AD has only recently been investigated in detail [117]. Currently, experimental and clinical findings indicate that glucocorticoids may represent a link between stress and development of AD-related pathology. "
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    • "The implication of such hormone signals in the pathology of dementia is supported by the evidence that phosphorylation of MAPT, which leads to neurofibrillary tangle formation and ultimately neurodegeneration, is regulated by the signaling effects of insulin and estradiol [77,78]. Similarly, the regulatory influence of thyroid hormone, melatonin, and corticotropin-raleasing factors on hippocampal tau phosphorylation has been documented in the literature [79-81]. "
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    • "Previous studies have reported the association between the hyperphosphorylation of tau and stress and stressactivated kinases (Sotiropoulos et al., 2011). Repeated stress exposure elicited cumulative effects on pTau and its sequestration in an insoluble, and potentially pathogenic , form (Rissman et al., 2007). Solas et al. (2010) showed that stressed aged rats showed significant increases in both pTau levels and activation of GSK3b. "
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    ABSTRACT: Chronic exposure to glucocorticoids might result not only in insulin resistance or cognitive deficits, but it is also considered as a risk factor for pathologies such as Alzheimer's disease. Propranolol is a β-adrenergic antagonist commonly used in the treatment of hypertension or acute anxiety. The effects of propranolol (5 mg/kg) have been tested in a model of chronic corticosterone administration (100 μg/ml, 4 wk) in drinking water. Corticosterone administration led to cognitive impairment in the novel object recognition test that was reversed by propranolol. Increased levels of Aβ in the hippocampus of corticosterone-treated mice were counteracted by propranolol treatment, purportedly through an increased IDE expression. Chronic corticosterone treatment induced responses characteristic of insulin resistance, as increased peripheral insulin levels, decreased activation of the insulin receptor (pIR) and decreased associated intracellular pathways (pAkt). These effects might be related to a decreased c-Jun N terminal kinase 1 expression. Again, propranolol was able to counteract all corticosterone-induced effects. One of the main kinases involved in tau phosphorylation, glycogen synthase kinase 3β (GSK3β), which is inactivated by phosphorylation by pAkt, was found to be decreased after corticosterone and increased after propranolol treatment. Concomitant changes in pTau expression were found. Overall, these data further strengthen the potential of propranolol as a therapeutic agent for pathologies associated with the interaction glucocorticoids-insulin resistance and the development of relevant cellular processes for Alzheimer's disease.
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