title: Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport.
abstract: Stress exposure or increased levels of corticotropin-releasing factor (CRF) induce hippocampal tau phosphorylation (tau-P) in rodent models, a process that is dependent on the type-1 CRF receptor (CRFR1). Although these preclinical studies on stress-induced tau-P provide mechanistic insight for epidemiological work that identifies stress as a risk factor for Alzheimer's disease (AD), the actual impact of stress-induced tau-P on neuronal function remains unclear. To determine the functional consequences of stress-induced tau-P, we developed a novel mouse neuronal cell culture system to explore the impact of acute (0.5hr) and chronic (2hr) CRF treatment on tau-P and integral cell processes such as axon transport. Consistent with in vivo reports, we found that chronic CRF treatment increased tau-P levels and caused globular accumulations of phosphorylated tau in dendritic and axonal processes. Furthermore, while both acute and chronic CRF treatment led to significant reduction in CREB activation and axon transport of brain-derived neurotrophic factor (BDNF), this was not the case with mitochondrial transport. Acute CRF treatment caused increased mitochondrial velocity and distance traveled in neurons, while chronic CRF treatment modestly decreased mitochondrial velocity and greatly increased distance traveled. These results suggest that transport of cellular energetics may take priority over growth factors during stress. Tau-P was required for these changes, as co-treatment of CRF with a GSK kinase inhibitor prevented CRF-induced tau-P and all axon transport changes. Collectively, our results provide mechanistic insight into the consequences of stress peptide-induced tau-P and provide an explanation for how chronic stress via CRF may lead to neuronal vulnerability in AD.
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America.
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Le
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America.
authors.forename: April M
authors.initials: AM
authors.lastname: Weissmiller
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America.
authors.forename: Louise
authors.initials: L
authors.lastname: Monte
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America.
authors.forename: Po Han
authors.initials: PH
authors.lastname: Lin
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America.
authors.forename: Tia C
authors.initials: TC
authors.lastname: Hexom
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America.
authors.forename: Orlangie
authors.initials: O
authors.lastname: Natera
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America.
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America.|Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rissman
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D013315:Stress, Psychological; D016875:tau Proteins / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018019:Receptors, Corticotropin-Releasing Hormone; D016875:tau Proteins; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone