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.

5 Reads
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: While the majority of studies have focused on the association between sex hormones and dementia, emerging evidence supports the role of other hormone signals in increasing dementia risk. However, due to the lack of an integrated view on mechanistic interactions of hormone signaling pathways associated with dementia, molecular mechanisms through which hormones contribute to the increased risk of dementia has remained unclear and capacity of translating hormone signals to potential therapeutic and diagnostic applications in relation to dementia has been undervalued. Using an integrative knowledge- and data-driven approach, a global hormone interaction network in the context of dementia was constructed, which was further filtered down to a model of convergent hormone signaling pathways. This model was evaluated for its biological and clinical relevance through pathway recovery test, evidence-based analysis, and biomarker-guided analysis. Translational validation of the model was performed using the proposed novel mechanism discovery approach based on 'serendipitous off-target effects'. Our results reveal the existence of a well-connected hormone interaction network underlying dementia. Seven hormone signaling pathways converge at the core of the hormone interaction network, which are shown to be mechanistically linked to the risk of dementia. Amongst these pathways, estrogen signaling pathway takes the major part in the model and insulin signaling pathway is analyzed for its association to learning and memory functions. Validation of the model through serendipitous off-target effects suggests that hormone signaling pathways substantially contribute to the pathogenesis of dementia. The integrated network model of hormone interactions underlying dementia may serve as an initial translational platform for identifying potential therapeutic targets and candidate biomarkers for dementia-spectrum disorders such as Alzheimer's disease.
    Journal of Translational Medicine 07/2013; 11(1):177. DOI:10.1186/1479-5876-11-177 · 3.93 Impact Factor
  • Source
    • "Next, we will investigate patterns of the effect of CRF on tissue Aβ and Aβ-plaque deposition with increasing age up to 18 months. The results further support the hypothesis that stress and stress factors, particularly CRF, will influence neuropathogenesis and cognitive function in AD [18] [20] [21] [22] [31] [32]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic stress has been suggested to influence the pathogenesis of Alzheimer's disease (AD); however, the mechanism underlying this influence remains unknown. In this study, we created a triple transgenic mouse model that overexpresses corticotrophin-releasing factor (CRF) and human amyloid-β protein precursor (AβPP), to investigate whether increases in the expression of CRF can mimic the effects of stress on amyloid metabolism and the neurodegeneration. Tg2576 mice that overexpresses human AβPP gene were crossbreed with Tetop-CRF (CRF) mice and CaMKII-tTA (tTA) mice to create a novel triple transgenic mouse model that conditioned overexpresses CRF in forebrain and overexpresses human AβPP (called AβPP+/CRF+/tTA+, or TT mice). Then we evaluated serial neuro-anatomical and behavioral phenotypes on TT mice using histological, biochemical, and behavioral assays. TT mice showed a Cushingoid-like phenotype starting at 3 months of age. At 6 months of age, these mice demonstrated increases in tissue-soluble amyloid-β (Aβ) and Aβ plaques in the cortex and hippocampus, as compared to control mice. Moreover, TT mice characterized substantial decreases in dendritic branching and dendritic spine density in pyramidal neurons in layer 4 of the frontal cortex and CA1 of the hippocampus. Finally, TT mice showed significantly impaired working memory and contextual memory, with a modest increase in anxiety-like behavior. Our results suggested genetic increases in the brain of CRF expression mimicked chronic stress on the effects of amyloid deposition, neurodegeneration, and behavioral deficits. The novel transgenic mouse model will provide a unique tool to further investigate the mechanisms between stress and AD.
    Journal of Alzheimer's disease: JAD 11/2011; 28(3):579-92. DOI:10.3233/JAD-2011-111328 · 4.15 Impact Factor
  • Source
    • "In cultured neurons, CRF 1 activation initiates CREB signaling which leads to phosphorylation of GSK3β (Bayatti et al., 2003; Facci et al., 2003). Recently, this link has also been reported in vivo, as stress induces GSK3β activation through phosphorylation at Tyr216 and increases ptau in wild type mice (Rissman et al., 2007). Nonetheless, other tau kinases, such as Fyn and Lck of the Src-kinase family (Scales et al., 2011), as well as various phosphatases such as protein phosphatase 2B (Qian et al., 2010), are also interesting candidates that may be linked to CRF 1 signaling and are planned targets of investigation by our laboratory. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Because overactivation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in Alzheimer's disease (AD), dysregulation of stress neuromediators may play a mechanistic role in the pathophysiology of AD. However, the effects of stress on tau phosphorylation are poorly understood, and the relationship between corticosterone and corticotropin-releasing factor (CRF) on both β-amyloid (Aβ) and tau pathology remain unclear. Therefore, we first established a model of chronic stress, which exacerbates Aβ accumulation in Tg2576 mice and then extended this stress paradigm to a tau transgenic mouse model with the P301S mutation (PS19) that displays tau hyperphosphorylation, insoluble tau inclusions and neurodegeneration. We show for the first time that both Tg2576 and PS19 mice demonstrate a heightened HPA stress profile in the unstressed state. In Tg2576 mice, 1 month of restraint/isolation (RI) stress increased Aβ levels, suppressed microglial activation, and worsened spatial and fear memory compared with nonstressed mice. In PS19 mice, RI stress promoted tau hyperphosphorylation, insoluble tau aggregation, neurodegeneration, and fear-memory impairments. These effects were not mimicked by chronic corticosterone administration but were prevented by pre-stress administration of a CRF receptor type 1 (CRF(1)) antagonist. The role for a CRF(1)-dependent mechanism was further supported by the finding that mice overexpressing CRF had increased hyperphosphorylated tau compared with wild-type littermates. Together, these results implicate HPA dysregulation in AD neuropathogenesis and suggest that prolonged stress may increase Aβ and tau hyperphosphorylation. These studies also implicate CRF in AD pathophysiology and suggest that pharmacological manipulation of this neuropeptide may be a potential therapeutic strategy for AD.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 10/2011; 31(40):14436-49. DOI:10.1523/JNEUROSCI.3836-11.2011 · 6.34 Impact Factor
Show more