Impact of Adverse Life Events on Neuroplasticity

慢性压力，如失去配偶或睡眠不足，可能会导致记忆障碍，增加AD的易感性。压力的实验模型表明，在心理社会或环境压力下，空间记忆、语境记忆和物体识别都会受到损害。然而，环境压力是否以及如何改变导致正常衰老和AD患者认知缺陷的细胞和分子变化仍有待确定。我们正在使用小鼠模型来测试这一假设，即慢性心理社会压力和睡眠剥夺将加速正常衰老和阿尔茨海默病患者认知障碍的发展。利用三转基因AD小鼠模型(3xTgAD小鼠)，我们正在确定慢性应激对淀粉样蛋白生成、tau病理、突触功能障碍以及学习和记忆障碍的影响。我们正在测试一种假设，即衰老和AD损害了适应性细胞应激反应途径，导致氧化应激增加，与脑源性神经营养因子(BDNF)和抗氧化酶等神经保护蛋白表达减少有关。在相关研究中，我们发现，在2型糖尿病模型中，暴饮暴食会导致神经内分泌应激系统的过度激活，肾上腺糖皮质激素水平的升高会损害海马区突触的可塑性和神经发生，这些应激相关的改变与认知功能障碍有关。有趣的是，经常锻炼和限制饮食能量可以通过上调神经营养因子BDNF的表达来抵消糖尿病对海马可塑性的不利影响。 慢性应激可能是阿尔茨海默病(AD)的危险因素，但大多数关于应激在AD模型中的影响的研究利用了临床上有疑问的急性不良应激源。因此，我们开展了一项研究，以确定慢性心理社会应激如何影响AD动物模型的行为和病理结果，并阐明潜在的机制。采用三转基因AD小鼠模型(3xTgAD小鼠)和非转基因对照小鼠，检测慢性轻度社会应激对血糖、血浆糖皮质激素、血浆胰岛素、焦虑和海马淀粉样蛋白(A&946；)、磷酸化tau(Ptau)和脑源性神经营养因子(BDNF)水平的影响。尽管对照组和3xTgAD小鼠在轻微的社会压力期间皮质酮水平都有所上升，但在6周应激期结束时，3xTgAD小鼠表现出更多的焦虑，A寡聚体和神经细胞内A的水平升高，脑源性神经营养因子水平下降，而对照组小鼠则没有。我们的发现表明，3xTgAD小鼠比对照组小鼠更容易受到慢性心理社会压力的影响，这种慢性压力会加剧A&A的积累，并损害神经营养信号。 一些带有丰富的淀粉样蛋白和/或异常磷酸化tau的阿尔茨海默病小鼠模型会出现记忆障碍。然而，多个非助记认知域，如注意力和执行控制，也在AD患者的早期受到影响。目前，尚不清楚淀粉样前体蛋白(APP)和tau基因的突变是否足以在该疾病的小鼠模型中引起类似AD样的注意力缺陷。为了解决这个问题，我们测试了3xTgAD小鼠(表达APPswe、PS1M146V和tauP301L突变)和野生型对照小鼠，测试了一种新开发的基于触摸屏的注意力和反应控制5选一系列反应时间测试。当任务的注意力需求较高时，3xTgAD小鼠对短的、空间上不可预测的刺激的反应不那么准确，而且也表现出比野生型小鼠更持久的反应的总体趋势。3xTgAD小鼠的注意障碍在两个方面与AD患者相似：第一，尽管3xTgAD小鼠最初的反应与野生型小鼠一样准确，但它们随后无法在任务持续时间内维持注意力；第二，胆碱酯酶抑制剂多奈哌齐(Aricept)增强了维持注意力的能力。这些发现表明，家族性AD突变不仅会影响记忆，还会导致注意力的显著损害，注意力是由前额叶皮质及其传入支持的认知领域。由于注意力缺陷可能会影响记忆编码和其他认知能力，我们的发现对AD动物模型的疾病机制和治疗方法的评估具有重要影响。

Chronic stresses such as loss of a spouse or sleep deprivation, may cause memory impairments and increase susceptibility to AD. Experimental models of stress demonstrate impairments in spatial memory, contextual memory and object recognition in response to psychosocial or environmental stress. Yet, it remains to be determined if and how environmental stress modifies the cellular and molecular alterations that result in cognitive deficits in normal aging and in AD. We are employing mouse models to test the hypothesis that chronic psychosocial stress and sleep deprivation will accelerate the development of cognitive impairment in normal aging and in AD. Using the triple-transgenic AD mouse model (3xTgAD mice) we are determining the effects of chronic stress on amyloidogenes, tau pathology, synaptic dysfunction and learning and memory impairment. We are testing the hypothesis that aging and AD compromise adaptive cellular stress response pathways resulting in increased oxidative stress associated with reduced expression of neuroprotective proteins such as brain-derived neurotrophic factor (BDNF) and antioxidant enzymes. In related studies we have found that, in a model of type 2 diabetes, overeating results in hyperactivation of the neuroendocrine stress system, and that elevated levels of adrenal glucocorticoids impair hippocampal synaptic plasticity and neurogenesis, and that these stress-related alterations are associated with a deficit in cognitive function. Interestingly, regular exercise and dietary energy restriction can counteract the adverse effects of diabetes on hippocampal plasticity by a mechanism involving up-regulation of the expression of the neurotrophic factor BDNF. Chronic stress may be a risk factor for developing Alzheimer's disease (AD), but most studies of the effects of stress in models of AD utilize acute adverse stressors of questionable clinical relevance. We therefore undertook a study to determine how chronic psychosocial stress affects behavioral and pathological outcomes in an animal model of AD, and to elucidate underlying mechanisms. A triple-transgenic mouse model of AD (3xTgAD mice) and nontransgenic control mice were used to test for an affect of chronic mild social stress on blood glucose, plasma glucocorticoids, plasma insulin, anxiety, and hippocampal amyloid β-particle (Aβ), phosphorylated tau (ptau), and brain-derived neurotrophic factor (BDNF) levels. Despite the fact that both control and 3xTgAD mice experienced rises in corticosterone during episodes of mild social stress, at the end of the 6-week stress period 3xTgAD mice displayed increased anxiety, elevated levels of Aβ oligomers and intraneuronal Aβ, and decreased brain-derived neurotrophic factor levels, whereas control mice did not. Our findings suggest 3xTgAD mice are more vulnerable than control mice to chronic psychosocial stress, and that such chronic stress exacerbates Aβ accumulation and impairs neurotrophic signaling. Several mouse models of AD with abundant β-amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the β-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V, and tauP301L mutations) and wild-type control mice on a newly developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild-type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects: first, although 3xTgAD mice initially responded as accurately as wild-type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD.