Alzheimer’s disease dementia risk in post-traumatic stress disorder: identification of common underlying mechanisms using rat models.

Abstract

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that can develop from exposure to a trauma. Studies have shown that people who have PTSD are susceptible to developing dementia, mostly Alzheimer’s disease (AD), suggesting common underlying risk factors in the comorbidity. Although several molecular pathways have been implicated in AD and PTSD, including oxidative stress, cellular apoptosis, synaptic dysfunction and stress dysregulation, the underlying neurobiological mechanisms linking AD and PTSD are less understood. This study, therefore, investigated the effect of trauma-like exposure in an amyloid-beta (Aβ) rat model of AD. Seventy-two adult male Sprague-Dawley rats were used throughout the study. The animals were randomly divided into four groups where they received either footshocks or Aβ(1-42) injection or were exposed to footshocks and Aβ(1-42) injection or remained naive. Following inductions, the animals were tested for cognitive, locomotor and anxiety-like behaviours. Thereafter, brain samples were collected for further neurochemical analyses. Our results show that footshocks increased anxiety-like behaviour and impaired fear memory extinction in Aβ(1-42) lesioned rats. A combination of footshocks and Aβ(1-42) also reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD (P) H: quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and increased the expression of Kelch-like ECH-associated protein 1 (Keap1) in the amygdala and hippocampus. Prior exposure to footshocks before Aβ(1-42) lesion caused a decrease in the number of crossing in the target quadrant of the Morris water maze test and reduced percentage alternation in the Y-maze test, indicating memory deficits. There was an interactive effect of footshocks and Aβ(1-42) lesion on the downregulation of BIN1 and the upregulation of NR2B in the hippocampus. There was also an interactive effect of footshocks and Aβ(1-42) lesion on the upregulation of FKBP5 in the hippocampus, amygdala, and PFC. Our finding suggests that footshock stress can exacerbate AD-like pathology via dysregulated redox balance, BIN1 downregulation, FKBP5 and NR2B upregulation, and increased apoptosis in the brain of Aβ(1-42)-lesioned rats. These molecular changes were associated with increased anxiety, impaired fear extinction and memory deficits. These findings, therefore, suggest common molecular mechanisms in PTSD and AD.

Isifo sengcindezi eba semva kwesehlakalo esibi i-post-traumatic stress disorder (i-PTSD) yisifo sokusebenzelana kwezinzwa nensebenzamqondo esidala wukwehlelwa yisehlakalo esibi. Ucwaningo selukhombise ukuthi abantu abane-PTSD basengcupheni yokuba nesifo sokukhohlwa, ikakhulukazi i- Alzheimer’s (i-AD), okuchaza ukuthi izimo eziyingcuphe enkulu ekubeni nezifo eziyizimbelambela. Nakuba izindlelamigudu eziningi zamamolekhyuli zisoleka kwi-AD ne-PTSD, okufaka nengcindezi ye-oxidative, i-cellular apoptosis, i-synaptic dysfunction kanye nokungalawuleki kwengcindezi, izindlelamigudu zempiliswanozinzwa nomzimba ezixhumanisa i-AD ne-PTSD akuqondwa ngokuphelele. Ngakho-ke lolu cwaningo, luphenye umthelela wokubekeka endaweni ecisho ibe yisehlakalo esinzima kwimodeli yamagundane i-amyloid-beta (Aβ) ye-rat model of AD. Amagundane amadala esilisa angamashumi ayisikhombisa nambili asetshenziswa kulolu cwaningo. Izilwane zehlukaniswa ngokungahleliwe zaba amaqembu amane lapho zanikwa khona amafootshocks noma umjovo we-Aβ(1-42) noma ayengathola i-footshocks nomjovo we-Aβ(1-42) noma ahlale engazi. Ukulandela ukwethulwa, izilwane zahlolelwa ukuziphatha kwazo ngokomcabango, ukuhamba nokuba nexhala. Emva kwalokho, amasampula obuchopho aqoqwa ukuze aphinde acutshungulelwe amanyurokhemikhali. Imiphumela yethu iveze ukuthi ama-footshocks enyuse ukuziphatha sakuba nexhala kanye nokuqeda ukukhumbula ukwesaba okugwegwile kuma-Aβ(1-42) onikwe amalesioned rats. Ingxubevange yefootshocks ne-Aβ(1-42) iphinde yehlisa ukuvela kwe-nuclear factor erythroid 2-related factor 2 (Nrf2), i-NAD (P) H: i-quinone oxidoreductase 1 (NQO1), i-heme oxygenase-1 (HO-1), kanye nokuvela okusezingeni eliphezulu kwe-Kelch-like ECH-associated protein 1 (Keap1) kwi-amygdala ne-hippocampus. Ukusondelana nama-footshocks kwangaphambi kwe-Aβ(1-42) kwdala ukwehla esibalweni sokuhlanganayo kwi-target quadrant yokuhlolwa kwe-Morris water maze test nenguqunguquko yephesenti kwi-Y-maze test, okuveza ukushoda kokukhumbula. Kwaba nomthelela onokungenelana wama-footshocks kanye ne-Aβ(1-42) lesion ekulawulenikwehlisa i-BIN1 nasekulawulenikukhuphula i-NR2B kwi-hippocampus. Kwaphinde kwaba nomthelela ongenelanayo we-footshocks ne- Aβ(1-42) lesion ekulawulenikukhuphula i- FKBP5 kwi-hippocampus, i-amygdala, ne- PFC. Esikutholile kuphakamise ukuthi ingcindezi ye-footshock ingabhebhezela isakhiwosifo esifuze i-AD nge-dysregulated redox balance, i-BIN1 downregulation, i-FKBP5 ne-NR2B upreguation, i-apoptosis ephezulu ebuchosheni be-Aβ(1-42)-ekuma-lesioned rats. Lezi zinguquko kumamolekhyuli zazihlotshaniswe nokwenyuka kwexhala, inqedakwesaba egwegwile nokulahlekelwa wukukhumbula. Ngakho-ke lokhu okutholakele, kuphakamisa izindlela ezejwayelekile zomumo wamamolekhyuli kwi-PTSD ne-AD.