Chronic psychosocial stress enhances long-term depression in a subthreshold amyloid-beta rat model of Alzheimer's disease.

In addition to genetic aspects, environmental factors such as stress may also play a critical role in the etiology of the late onset, sporadic Alzheimer's disease (AD). The present study examined the effect of chronic psychosocial stress in a sub-threshold Aβ (subAβ) rat model of AD on long-term depression by two techniques: electrophysiological recordings of synaptic plasticity in anesthetized rats, and immunoblot analysis of memory- and AD-related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAβ rat model of AD, which was intended to represent outwardly normal individuals with a pre-disposition to AD, was induced by continuous infusion of 160 pmol/day Aβ₁₋₄₂ via a 14-day i.c.v. osmotic pump. Results from electrophysiological recordings showed that long-term depression evoked in stress/subAβ animals was significantly enhanced compared with that in animals exposed to stress or subAβ infusion alone. Molecular analysis of various signaling molecules 1 h after induction of long-term depression revealed an increase in the levels of calcineurin and phosphorylated CaMKII in groups exposed to stress compared with other groups. The levels of the brain-derived neurotrophic factor (BDNF) were significantly decreased in stress/subAβ animals but not in stress or subAβ animals. In addition, the levels of beta-site amyloid precursor protein cleaving enzyme were markedly increased in stress/subAβ. These findings suggest that chronic stress may accelerate the impairment of synaptic plasticity and consequently cognition in individuals 'at-risk' for AD.

Tran TT ，Srivareerat M ，Alhaider IA ，Alkadhi KA ... -  《-》

Chronic psychosocial stress triggers cognitive impairment in a novel at-risk model of Alzheimer's disease.

Although it is generally accepted that Abeta contributes to the pathogenesis of Alzheimer's disease (AD), other factors that impact the severity and time of onset of the disease are not well known. Aside from genetic factors, environmental factors such as stress may also play a critical role in the manifestation of AD. The present study examined the effect of chronic psychosocial stress in an at-risk, subthreshold Abeta (subAbeta) rat model of AD by three approaches: learning and memory tests in the radial arm water maze, electrophysiological recordings of long-term potentiation (LTP) in anesthetized rats, and immunoblot analysis of learning- and memory-related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAbeta rat model of AD was induced by continuous i.c.v. infusion of 160 pmol/day Abeta(1-42) via a 14-day osmotic pump. Behavioral tests and electrophysiological recordings showed that subAbeta rats were not significantly different from control rats. However, chronically stressed subAbeta rats showed more significant impairment of cognitive functions and early-phase LTP (E-LTP) than that caused by stress alone. Molecular analysis of essential signaling molecules after induction of E-LTP revealed an increase in the levels of p-CaMKII in control as well as subAbeta infused rats, but not in stressed or stressed at-risk rats. In addition, compared to unstimulated control, the levels of both total CaMKII and calcineurin were increased in all stimulated animals groups after HFS. These findings suggest that the stress-induced alterations may accelerate the impairment of cognition and synaptic plasticity in individuals "at-risk" for AD.

Tran TT ，Srivareerat M ，Alkadhi KA 《-》

Chronic psychosocial stress accelerates impairment of long-term memory and late-phase long-term potentiation in an at-risk model of Alzheimer's disease.

Although it is generally agreed that Aβ contributes to the pathogenesis of AD, its precise role in AD and the reason for the varying intensity and time of onset of the disease have not been elucidated. In addition to genetic factors, environmental issues such as stress may also play a critical role in the etiology of AD. This study examined the effect of chronic psychosocial stress in an at-risk (treatment with a subpathogenic dose of Aβ; "subAβ") rat model of AD on long-term memory by three techniques: memory tests in the radial arm water maze, electrophysiological recordings of synaptic plasticity in anesthetized rats, and immunoblot analysis of learning- and long-term memory-related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAβ rat model of AD was induced by continuous infusion of 160 pmol/day Aβ(1-42) via a 14-day i.c.v. osmotic pump. All tests showed that subAβ rats were not different from control rats. Result from behavioral tests and electrophysiological recordings showed that infusion of subAβ in chronically stressed rats (stress/subAβ group) caused significant impairment of cognitive functions and late-phase long-term potentiation (L-LTP). Molecular analysis of various signaling molecules after expression of L-LTP, revealed an increase in the levels of p-CREB in control, stress, and subAβ rats, but not in the stress/subAβ rats. These findings suggest that the chronic stress-induced molecular alteration may accelerate the impairment of cognition and synaptic plasticity in individuals "at-risk" for AD.

Tran TT ，Srivareerat M ，Alkadhi KA 《-》

Chronic psychosocial stress exacerbates impairment of cognition and long-term potentiation in beta-amyloid rat model of Alzheimer's disease.

Srivareerat M ，Tran TT ，Alzoubi KH ，Alkadhi KA ... -  《-》

Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by increased deposition of beta-amyloid (Aβ) peptides and progressive cholinergic dysfunction in regions of the brain involved in learning and memory processing. In AD, progressive accumulation of Aβ peptide impairs nicotinic acetylcholine receptor (nAChR) function by an unknown mechanism believed to involve α(7)- and α(4)β(2)-nAChR blockade. The three approaches of the current study evaluated the effects of chronic nicotine treatment in the prevention of Aβ-induced impairment of learning and short-term memory. Rat AD model was induced by 14-day i.c.v. osmotic pump infusion of a 1:1 mixture of 300 pmol/day Aβ(1-40)/Aβ(1-42) or Aβ(40-1) (inactive peptide, control). The effect of nicotine (2 mg/(kg day)) on Aβ-induced spatial learning and memory impairments was assessed by evaluation of performance in the radial arm water maze (RAWM), in vivo electrophysiological recordings of early-phase long-term potentiation (E-LTP) in urethane-anesthetized rats, and immunoblot analysis to determine changes in the levels of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), Aβ and memory-related proteins. The results indicate that 6 weeks of nicotine treatment reduced the levels of Aβ(1-40) and BACE1 peptides in hippocampal area CA1 and prevented Aβ-induced impairment of learning and short-term memory. Chronic nicotine also prevented the Aβ-induced inhibition of basal synaptic transmission and LTP in hippocampal area CA1. Furthermore, chronic nicotine treatment prevented the Aβ-induced reduction of α(7)- and α(4)-nAChR. These effects of nicotine may be due, at least in part, to upregulation of brain derived neurotropic factor (BDNF).

Srivareerat M ，Tran TT ，Salim S ，Aleisa AM ，Alkadhi KA ... -  《-》