RT Journal Article
SR Electronic
T1 Posttraumatic Stress Disorder-Like Induction Elevates β-Amyloid Levels, Which Directly Activates Corticotropin-Releasing Factor Neurons to Exacerbate Stress Responses
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2612
OP 2623
DO 10.1523/JNEUROSCI.3333-14.2015
VO 35
IS 6
A1 Nicholas J. Justice
A1 Longwen Huang
A1 Jin-Bin Tian
A1 Allysa Cole
A1 Melissa Pruski
A1 Albert J. Hunt, Jr.
A1 Rene Flores
A1 Michael X. Zhu
A1 Benjamin R. Arenkiel
A1 Hui Zheng
YR 2015
UL http://www.jneurosci.org/content/35/6/2612.abstract
AB 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.