اجرای تاخیرهای ورزش دژنراسیون عصبی در آمیگدال و هیپوکامپ بیماری آلزایمر (APP / PS1) موش های ترانس

Alzheimer’s disease (AD) is an age-related neurodegenerative disease. Post-mortem examination and brain imaging studies indicate that neurodegeneration is evident in the hippocampus and amygdala of very early stage AD patients. Exercise training is known to enhance hippocampus- and amygdala-associated neuronal function. Here, we investigated the effects of exercise (running) on the neuronal structure and function of the hippocampus and amygdala in APP/PS1 transgenic (Tg) mice. At 4-months-old, an age before amyloid deposition, the amygdala-associated, but not the hippocampus-associated, long-term memory was impaired in the Tg mice. The dendritic complexities of the amygdalar basolateral neurons, but not those in the hippocampal CA1 and CA3 neurons, were reduced. Furthermore, the levels of BDNF/TrkB signaling molecules (i.e. p-TrkB, p-Akt and p-PKC) were reduced in the amygdala, but not in the hippocampus of the 4-month-old Tg mice. The concentrations of Aβ40 and Aβ42 in the amygdala were higher than those in the hippocampus. Ten weeks of treadmill training (from 1.5- to 4-month-old) increased the hippocampus-associated memory and dendritic arbor of the CA1 and CA3 neurons, and also restored the amygdala-associated memory and the dendritic arbor of amygdalar basolateral neurons in the Tg mice. Similarly, exercise training also increased the levels of p-TrkB, p-AKT and p-PKC in the hippocampus and amygdala. Furthermore, exercise training reduced the levels of soluble Aβ in the amygdala and hippocampus. Exercise training did not change the levels of APP or RAGE, but significantly increased the levels of LRP-1 in both brain regions of the Tg mice. In conclusion, our results suggest that tests of amygdala function should be incorporated into subject selection for early prevention trials. Long-term exercise protects neurons in the amygdala and hippocampus against AD-related degeneration, probably via enhancements of BDNF signaling pathways and Aβ clearance. Physical exercise may serve as a means to delay the onset of AD.

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. Pathologically, AD is characterized by extracellular deposition of Aβ peptides in the amyloid plaques and intracellular accumulation of hyperphosphorylated tau in the neurofibrillary tangles. Biochemical and morphological studies suggest that neuronal synaptic connections are greatly reduced in AD brains (Larson et al., 1999 and Small et al., 2001). The most frequent and early clinical symptom of AD is memory impairment, in particular short-term memory (Albert et al., 2011 and Thies and Bleiler, 2013). Atrophy of the medial temporal lobe, a critical region involved in memory formation, is a recognized marker for AD (Duara et al., 2008 and Jobst et al., 1994). Volumetric measurements of the hippocampus and amygdala, both residing in the medial temporal lobe, have been used to predict the cognitive status of the elderly (den Heijer et al., 2006) and to assist the clinical diagnosis of AD (Callen et al., 2001, Heun et al., 1997 and Tang et al., 2014). Hippocampal and amygdalar memory impairments are already evident in the prodromal stage of AD (Palmer et al., 2007). In patients with MCI due to AD, atrophy (Fjell et al., 2010, Mizuno et al., 2000, Poulin et al., 2011 and Roh et al., 2011) and deposition of amyloid plaques (Haroutunian et al., 1998 and Markesbery et al., 2006) in the hippocampus and amygdala are more pronounced than in normal individuals of similar ages. Furthermore, the levels of Aβ42, total tau and p-tau in the cerebrospinal fluid (CSF) in patients with MCI are known to correlate with volumes of the hippocampus and amygdala (Fjell et al., 2010). These findings suggest that degeneration in the hippocampus and amygdala are crucial in clinical AD symptom manifestation. However, most scientific efforts focus only on hippocampal degeneration and leave amygdala less explored. Increased physical activity has been shown to improve cognitive performance in humans at various ages (Hillman, Erickson, & Kramer, 2008). Exercise is also known to improve the ability of AD patients to perform daily activities (Rolland et al., 2007). In animal studies, running improves the performance of hippocampus- and amygdala-associated learning and memory (Lin et al., 2012, Liu et al., 2009 and van Praag, 2009). The beneficial effect of running exercise is, at least partially, contributed by the enhanced BDNF–/TrkB signaling pathway (Lin et al., 2012 and Liu et al., 2009). Therefore, we hypothesize that exercise training could delay or prevent AD progression by protecting neurons in the hippocampus and amygdala. In this study, we aimed to investigate the effect of exercise on neurodegeneration in the hippocampus and amygdala of young APP/PS1 double transgenic (Tg) mice, to mimic the prodromal stage of AD. We chose mandatory treadmill running as the exercise paradigm in order to control the precise intensity and duration of the exercise. The Tg mice were investigated at four months of age, before the typical onset time of amyloid deposition which occurs at around 6-months-old. The wild-type (Wt) littermates served as controls. After 10 weeks of exercise training, the learning and memory performance, dendritic morphology and synaptic protein expressions were examined. We chose the Pavlovian fear conditioning task to evaluate learning and memory performance because this task allowed us to assess both hippocampus- and amygdala-associated learning and memory functions (Phillips & LeDoux, 1992). Single neurons in the hippocampal CA1 and CA3 regions and the basolateral amygdala (BLA) were labeled by fluorescent dye injection to determine the changes in dendritic arborization. As BDNF/TrkB signaling pathways are known to regulate neuroplasticity, the levels of BDNF/TrkB and their downstream signaling proteins (i.e. PKC, AKT and ERK) in the hippocampus and amygdala were measured. Finally, the concentrations of Aβ (40 and 42), APP, RAGE, and LRP1 were also determined.

This study analyzed the effects of Ex on hippocampus and amygdala associated neurodegeneration in the Tg mice. Our results, at behavioral, morphological, and molecular levels demonstrated that neurodegeneration has already occurred in the hippocampus and amygdala of young (pre-amyloid deposition) Tg mice, with more severe degeneration present in the amygdala. These observations, together with previous findings, strongly suggest that tests of amygdala function should be incorporated into subject selection for early prevention trials. We also show that Ex counteracts the Tg-induced neurodegeneration by improving the structure and function of neurons in the hippocampus and amygdala. Exercise enhances the BDNF signaling pathways and Aβ clearance, both of which may account for the protective effects of Ex. Thus, long-term physical exercise may serve as an effective strategy to delay the onset of AD.