title: Posttraumatic stress disorder-like induction elevates β-amyloid levels, which directly activates corticotropin-releasing factor neurons to exacerbate stress responses.
abstract: Recent studies have found that those who suffer from posttraumatic stress disorder (PTSD) are more likely to experience dementia as they age, most often Alzheimer's disease (AD). These findings suggest that the symptoms of PTSD might have an exacerbating effect on AD progression. AD and PTSD might also share common susceptibility factors such that those who experience trauma-induced disease were already more likely to succumb to dementia with age. Here, we explored these two hypotheses using a mouse model of PTSD in wild-type and AD model animals. We found that expression of human familial AD mutations in amyloid precursor protein and presenilin 1 leads to sensitivity to trauma-induced PTSD-like changes in behavioral and endocrine stress responses. PTSD-like induction, in turn, chronically elevates levels of CSF β-amyloid (Aβ), exacerbating ongoing AD pathogenesis. We show that PTSD-like induction and Aβ elevation are dependent on corticotropin-releasing factor (CRF) receptor 1 signaling and an intact hypothalamic-pituitary-adrenal axis. Furthermore, we show that Aβ species can hyperexcite CRF neurons, providing a mechanism by which Aβ influences stress-related symptoms and PTSD-like phenotypes. Consistent with Aβ causing excitability of the stress circuitry, we attenuate PTSD-like phenotypes in vivo by lowering Aβ levels during PTSD-like trauma exposure. Together, these data demonstrate that exposure to PTSD-like trauma can drive AD pathogenesis, which directly perturbs CRF signaling, thereby enhancing chronic PTSD symptoms while increasing risk for AD-related dementia.
authors: Institute of Molecular Medicine, Program in Neuroscience, and Huffington Center on Aging and Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas 77030, and Nicholas.J.Justice@uth.tmc.edu.
authors: Nicholas J
authors: NJ
authors: Justice
authors: Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas 77030, and Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030.
authors: Longwen
authors: L
authors: Huang
authors: Department of Integrative Biology and Pharmacology, University of Texas Health Sciences Center, Houston, Texas 77030.
authors: Jin-Bin
authors: JB
authors: Tian
authors: Huffington Center on Aging and.
authors: Allysa
authors: A
authors: Cole
authors: Institute of Molecular Medicine.
authors: Melissa
authors: M
authors: Pruski
authors: Institute of Molecular Medicine, Program in Neuroscience, and.
authors: Albert J
authors: http://orcid.org/0000-0002-9738-7621
authors: AJ
authors: Hunt
authors: Institute of Molecular Medicine.
authors: Rene
authors: R
authors: Flores
authors: Department of Integrative Biology and Pharmacology, University of Texas Health Sciences Center, Houston, Texas 77030.
authors: Michael X
authors: MX
authors: Zhu
authors: Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas 77030, and Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030.
authors: Benjamin R
authors: BR
authors: Arenkiel
authors: Huffington Center on Aging and Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas 77030, and.
authors: Hui
authors: H
authors: Zheng
mesh_terms: D000305:Adrenal Cortex Hormones / Q000134:cerebrospinal fluid; D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D016466:CHO Cells; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D003412:Cricetulus; D055879:Gene Knock-In Techniques; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D061251:Primary Cell Culture; D013313:Stress Disorders, Post-Traumatic / Q000378:metabolism* / Q000523:psychology; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology
chemical_list: D000305:Adrenal Cortex Hormones; D016229:Amyloid beta-Peptides; D003346:Corticotropin-Releasing Hormone; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; PTSD; crf; crfr1; crh; stress