Stress is implicated as a contributing factor in age-related neurodegenerative disorders such as Alzheimer's Disease (AD), which is defined by the accumulation of plaques composed of ?-amyloid (A?) and neurofibrillary tangles consisting of hyperphosphorylated forms of the cytoskeletal protein, tau. The means by which stress contributes to these AD hallmarks remain to be elucidated. We have found that acute exposure to an emotional stressor (physical restraint) elicits robust increases in tau phosphorylation (tau-P) in mouse hippocampus, a pivotal structure in learning and memory. We fail to implicate stress-induced glucocorticoid secretion in this respect, but find the response is abolished by disruption of signaling via the type 1 corticotropin-releasing factor receptor (CRFR1) and exaggerated in CRFR2-deficient mice. Moreover, while acute restraint-induced increments in hippocampal tau-P were short-lived, repeated daily stress sessions (14 days) led to cumulative increases in tau-P and its sequestration in insoluble, pre-pathogenic form.
Five aims employing a range of biochemical, histochemical/neuroanatomical and behavioral assays are proposed to further explore the role of stress and the CRF signaling system in mechanisms of AD pathogenesis. First, we will determine whether acute restraint-induced tau-P generalizes to other brain regions afflicted in AD, other stressors that differ in potency and kind, and probe the biochemical mechanisms underlying the response. Second, to define the underlying circuitry, we will characterize sites of stress-induced tau-P (and cellular activation) using transgenic mice that report CRFR expression, use combined retrograde tracing and histochemical methods to identify sources of CRF ligand-containing inputs to hippocampus, and then test experimentally the involvement of implicated neural pathways. Third, we will characterize the effects of repeated exposure to emotional stress on tau-P and A? production, and explore their mechanisms and CRFR-dependence. Immunoelectron microscopy will be used to pursue preliminary evidence that repeated stress results in the formation of pre-pathogenic tau aggregates. Fourth, we will assess the ability of stress exposure over a significant portion of lifespan to modulate histochemical, biochemical and behavioral indices of tau and A? pathogenesis in a murine model of AD, as well as in normal aging, and determine the CRFR-dependence of observed effects. Finally, we will take advantage of a unique repository of brain material from human AD patients thoroughly characterized antemortem on indices of stress sensitivity and cognitive impairment to determine how the expression of CRF signaling molecules is altered in AD, and the extent to which such alterations may correlate with behavioral measures. The results are expected to clarify (1) the capacity of emotional stress exposure to promulgate AD- related tau and A? pathogenesis, (2) the neural circuitry and biochemical mechanisms underlying such effects, and (3) the extent to which they are mediated/modulated by signaling through CRFRs, which may well prove to warrant consideration as targets for therapeutic intervention in AD.

Public Health Relevance

Alzheimer's Disease is a progressive, age-related neurodegenerative disorder affecting memory and other higher brain functions, which currently afflicts roughly five million Americans. This project builds on our recent finding that a key biochemical process involved in Alzheimer's Disease can be stimulated by single or repeated exposures to stresses of the kind encountered in everyday life, and that blocking a particular neurotransmitter system in the brain can eliminate this potentially deleterious effect of stress. In deepening understanding of the brain circuits and mechanisms underlying these effects, the proposed experiments will evaluate a legitimate candidate target for the development of drugs that may slow or prevent the progression of Alzheimer's Disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
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Miller, Marilyn
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Salk Institute for Biological Studies
La Jolla
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Zlatar, Zvinka Z; Bischoff-Grethe, Amanda; Hays, Chelsea C et al. (2016) Higher Brain Perfusion May Not Support Memory Functions in Cognitively Normal Carriers of the ApoE ε4 Allele Compared to Non-Carriers. Front Aging Neurosci 8:151
Le, Michelle H; Weissmiller, April M; Monte, Louise et al. (2016) Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport. PLoS One 11:e0147250
Zhang, Cheng; Kuo, Ching-Chang; Moghadam, Setareh H et al. (2016) Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease. Alzheimers Dement 12:527-37
Steinmetz, Danielle; Ramos, Eugenia; Campbell, Shannon N et al. (2015) Reproductive Stage and Modulation of Stress-Induced Tau Phosphorylation in Female Rats. J Neuroendocrinol 27:827-34
Hanson, Angela J; Bayer, Jennifer L; Baker, Laura D et al. (2015) Differential Effects of Meal Challenges on Cognition, Metabolism, and Biomarkers for Apolipoprotein E ɛ4 Carriers and Adults with Mild Cognitive Impairment. J Alzheimers Dis 48:205-18
Campbell, Shannon N; Zhang, Cheng; Roe, Allyson D et al. (2015) Impact of CRFR1 Ablation on Amyloid-β Production and Accumulation in a Mouse Model of Alzheimer's Disease. J Alzheimers Dis 45:1175-84
Zhang, Cheng; Kuo, Ching-Chang; Moghadam, Setareh H et al. (2015) Corticotropin-Releasing Factor Receptor-1 Antagonism Reduces Oxidative Damage in an Alzheimer���s Disease Transgenic Mouse Model. J Alzheimers Dis 45:639-50
Campbell, Shannon N; Zhang, Cheng; Monte, Louise et al. (2015) Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor. J Alzheimers Dis 43:967-76
Zhang, Cheng; Rissman, Robert A; Feng, June (2015) Characterization of ATP alternations in an Alzheimer's disease transgenic mouse model. J Alzheimers Dis 44:375-8
Donohue, Michael C; Moghadam, Setareh H; Roe, Allyson D et al. (2015) Longitudinal plasma amyloid beta in Alzheimer's disease clinical trials. Alzheimers Dement 11:1069-79

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