Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport

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 epid...

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Veröffentlicht in:PloS one 2016-01, Vol.11 (1), p.e0147250-e0147250
Hauptverfasser: Le, Michelle H, Weissmiller, April M, Monte, Louise, Lin, Po Han, Hexom, Tia C, Natera, Orlangie, Wu, Chengbiao, Rissman, Robert A
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container_title PloS one
container_volume 11
creator Le, Michelle H
Weissmiller, April M
Monte, Louise
Lin, Po Han
Hexom, Tia C
Natera, Orlangie
Wu, Chengbiao
Rissman, Robert A
description 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.
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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. 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subjects Alzheimer's disease
Animal models
Animals
Axonal transport
Axonal Transport - drug effects
Axonal Transport - physiology
Brain
Brain-derived neurotrophic factor
Brain-Derived Neurotrophic Factor - metabolism
Cell culture
Cells, Cultured
Corticotropin-releasing hormone
Corticotropin-Releasing Hormone - pharmacology
Cyclic AMP response element-binding protein
Dementia
Enzyme inhibitors
Epidemiology
Exposure
Female
Genetic aspects
Growth factors
Health risks
Hippocampus
Hippocampus - cytology
Hippocampus - drug effects
Hippocampus - metabolism
Hypotheses
Kinases
Mice
Mice, Inbred C57BL
Mitochondria
Neurodegeneration
Neurodegenerative diseases
Neurons - cytology
Neurons - drug effects
Neurons - metabolism
Neuropathology
Neurosciences
Phosphorylation
Phosphorylation - drug effects
Physiological aspects
Proteins
Receptors, Corticotropin-Releasing Hormone - metabolism
Risk factors
Rodents
Stress
Stress response
Stress, Psychological
Stresses
Tau protein
tau Proteins - metabolism
Transport
Velocity
title Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T04%3A42%3A50IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Functional%20Impact%20of%20Corticotropin-Releasing%20Factor%20Exposure%20on%20Tau%20Phosphorylation%20and%20Axon%20Transport&rft.jtitle=PloS%20one&rft.au=Le,%20Michelle%20H&rft.date=2016-01-20&rft.volume=11&rft.issue=1&rft.spage=e0147250&rft.epage=e0147250&rft.pages=e0147250-e0147250&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0147250&rft_dat=%3Cgale_plos_%3EA440689642%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1758478537&rft_id=info:pmid/26790099&rft_galeid=A440689642&rft_doaj_id=oai_doaj_org_article_12c5997d44334087b2c839abeee24465&rfr_iscdi=true