Chronic stress-induced memory deficits are reversed by regular exercise via AMPK-mediated BDNF induction.

Chronic stress has a detrimental effect on neurological insults, psychiatric deficits, and cognitive impairment. In the current study, chronic stress was shown to impair learning and memory functions, in addition to reducing in hippocampal Adenosine monophosphate-activated protein kinase (AMPK) activity. Similar reductions were also observed for brain-derived neurotrophic factor (BDNF), synaptophysin, and post-synaptic density-95 (PSD-95) levels, all of which was counter-regulated by a regime of regular and prolonged exercise. A 21-day restraint stress regimen (6 h/day) produced learning and memory deficits, including reduced alternation in the Y-maze and decreased memory retention in the water maze test. These effects were reversed post-administration by a 3-week regime of treadmill running (19 m/min, 1 h/day, 6 days/week). In hippocampal primary culture, phosphorylated-AMPK (phospho-AMPK) and BDNF levels were enhanced in a dose-dependent manner by 5-amimoimidazole-4-carboxamide riboside (AICAR) treatment, and AICAR-treated increase was blocked by Compound C. A 7-day period of AICAR intraperitoneal injections enhanced alternation in the Y-maze test and reduced escape latency in water maze test, along with enhanced phospho-AMPK and BDNF levels in the hippocampus. The intraperitoneal injection of Compound C every 4 days during exercise intervention diminished exercise-induced enhancement of memory improvement during the water maze test in chronically stressed mice. Also, chronic stress reduced hippocampal neurogenesis (lower Ki-67- and doublecortin-positive cells) and mRNA levels of BDNF, synaptophysin, and PSD-95. Our results suggest that regular and prolonged exercise can alleviate chronic stress-induced hippocampal-dependent memory deficits. Hippocampal AMPK-engaged BDNF induction is at least in part required for exercise-induced protection against chronic stress.

Hippocampal neuronal death induced by kainic acid and restraint stress is suppressed by exercise.

The present study investigated whether chronic exercise suppressed hippocampal neuronal death due to repeated stress followed by i.c.v. kainic acid (KA) injection, and whether cAMP response element-binding protein (CREB), mitogen-activated protein kinase (MAPKs), and calcium/calmodulin-dependent protein kinase II (CaMKII) activation contributed to the neuroprotective effect in this experimental paradigm. To achieve the objective, mice were subjected to treadmill running for 8 weeks (19 m/min, 1 h/d, 5 d/wk) followed by seven consecutive days of repeated restraint stress (2 h/d), and then i.c.v. injection of KA (0.05 µg/5 µL). Hippocampal neuronal death was assessed using Nissl staining, and protein levels were measured using Western blot and immunohistochemical analysis. Hippocampal neuronal loss in mice subjected to restraint stress and KA injection was exacerbated compared with KA injection alone, which was reversed in the hippocampal CA3 region with prior chronic exercise. To further identify the neuroprotective effects of chronic exercise administration on hippocampal insults by repeated stress, levels of stress-related factors were measured. First, there was no significant difference in serum corticosterone and glucocorticoid (Gc) receptor levels in mice with restraint alone and restraint combined with prior chronic exercise. Second, malondialdehyde (MDA) and nitrite levels were significantly enhanced in restrained mice and were revered in restraint with chronic exercise. However, pCREB levels in the hippocampus in restraint mice with chronic exercise were profoundly increased compared with levels in restraint-alone mice. Among the MAPKs, pERK1/2 levels in restraint mice with chronic exercise were significantly higher than levels in mice with restraint alone. Furthermore, pCaMKII levels in restraint mice with chronic exercise were markedly elevated compared with levels in mice after restraint alone. Prior chronic exercise suppressed KA-induced hippocampal neuronal death in hippocampal CA3 region in restrained mice via declined ROS levels, which was lower MDA and nitrite levels, and activation of CREB, which was mediated by ERK1/2 and CaMKII, suggesting that chronic exercise exerts a protective effect on excitatory neurodegenerative disorders including epileptic seizure.

Tau overexpression in transgenic mice induces glycogen synthase kinase 3beta and beta-catenin phosphorylation.

The abnormal phosphorylations of tau, GSK3beta, and beta-catenin have been shown to perform a crucial function in the neuropathology of Alzheimer's disease (AD). The primary objective of the current study was to determine the manner in which overexpressed htau23 interacts and regulates the behavior and phosphorylation characteristics of tau, GSK3beta, and beta-catenin. In order to accomplish this, transgenic mice expressing neuron-specific enolase (NSE)-controlled human wild-type tau (NSE/htau23) were created. Transgenic mice evidenced the following: (i) tendency toward memory impairments at later stages, (ii) dramatic overexpression of the tau transgene, coupled with increased tau phosphorylation and paired helical filaments (PHFs), (iii) high levels of GSK3beta phosphorylation with advanced age, resulting in increases in the phosphorylations of tau and beta-catenin, (iv) an inhibitory effect of lithium on the phosphorylations of tau, GSK3beta, and beta-catenin, but not in the non-transgenic littermate group. Therefore, the overexpression of NSE/htau23 in the brains of transgenic mice induces abnormal phosphorylations of tau, GSK3beta, and beta-catenin, which are ultimately linked to neuronal degeneration in cases of AD. These transgenic mice are expected to prove useful for the development of new drugs for the treatment of AD.