Plasticity circuits in Alzheimers disease

 描述(由申请人提供)：海马神经发生与可塑性、学习和记忆以及在新环境中的体验的调节有关。然而，神经发生在学习和记忆缺陷以及阿尔茨海默病(AD)中的作用尚未完全阐明。阿尔茨海默病(AD)是一种以记忆丧失和认知衰退为特征的神经退行性疾病。我们已经证明，在家族性阿尔茨海默病(FAD)的动物模型中，海马神经发生在生命早期受到损害。神经发生缺陷先于症状的出现以及学习和记忆障碍的出现，表明神经发生缺陷可能在认知衰退的发展中发挥作用。此外，我们还表明，小鼠在丰富环境中的经历可以挽救受损的神经发生，并减轻神经病理。然而，目前尚不清楚阿尔茨海默病患者神经发生的损害是否是原因，以及上调神经发生是否会挽救认知缺陷。为了解决这个问题，我们建立了小鼠模型，在这个模型中，神经发生是可调控的。具体地说，APPSWE/PS1ΔE9中神经发生的消融是通过更昔洛韦诱导表达修改版本的单纯疱疹病毒胸苷激酶的神经前体细胞(APPSwePS1 HSV E9/Nestin-δ-HSV-TK小鼠)实现的。通过他莫昔芬诱导APPSwePS1ΔE9/ΔE9/Baxlox/lox小鼠神经前体细胞(APPSwePS1 Baxlox E9/Nestin-CreerT2/Baxlox/lox小鼠)的BAX消融，促进APPSWE/PS1 Baxlox E9小鼠的神经发生。在一项初步研究中，我们发现更昔洛韦治疗的APPSwePS1ΔE9/Nestn-δ-HSV-TK小鼠的神经发生程度显著降低，并伴有上下文编码、模式分离和新对象识别方面的缺陷，早在三个月大时。有趣的是，我们观察到这些小鼠的海马区淀粉样蛋白沉积比赋形剂处理的APPSwePS1ΔE9/Nestin-δ-HSV-TK或APPSwePS1ΔE9小鼠更多。综上所述，这些观察结果表明，海马神经发生受损在AD认知障碍和神经病理的发展中起关键作用，而神经发生的增强将恢复这些缺陷。实验将确定FAD小鼠神经发生的丧失或增加对海马神经前体细胞和新神经元的增殖、存活和细胞命运决定的程度(特定目标1)、神经病理进展(特定目标2)和学习记忆(特定目标3)的影响。在具体目标4中，我们将研究轻度认知障碍(MCI)和AD患者脑组织中神经发生的程度、认知功能水平和神经病理之间的关系。这些实验将确定神经发生在阿尔茨海默病中的作用，并导致基于神经发生的疾病认知缺陷治疗的发展。

 DESCRIPTION (provided by applicant): Hippocampal neurogenesis is implicated in regulation of plasticity, learning and memory and experience in novel environments. However, the role of neurogenesis in learning and memory deficits and in Alzheimer's disease (AD), a neurodegenerative disease characterized by loss of memory and cognitive decline, is not fully elucidated. We have shown that hippocampal neurogenesis is impaired early in life in animal models of Familial Alzheimer's disease (FAD). Deficits in neurogenesis precede onset of hallmarks and onset of learning and memory impairments, suggesting that defective neurogenesis may play a role in the development of cognitive decline. In addition, we have shown that experience of mice in environmental enrichment rescues impaired neurogenesis and attenuate neuropathology. However, it is not clear whether impairments in neurogenesis in AD are causative and whether up regulation of neurogenesis would rescue cognitive deficits. To address that, we generated mouse models, in which neurogenesis is regulatable. Specifically, ablation of neurogenesis in APPswe/PS1ΔE9 was achieved by ganciclovir-induced depletion of neural progenitor cells expressing a modified version of the herpes simplex virus thymidine kinase (APPswePS1ΔE9/nestin-δ-HSV-TK mice). Enhancement of neurogenesis in APPswe/PS1ΔE9 mice was achieved by tamoxifen-induced ablation of Bax in neural progenitor cells (APPswePS1ΔE9/nestin-CreERT2/Baxlox/lox mice). In a preliminary study we show that ganciclovir-treated APPswePS1ΔE9/nestin-δ-HSV-TK mice exhibit significantly reduced extent of neurogenesis accompanied by deficits in contextual encoding, pattern separation and novel object recognition, as early as three months of age. Intriguingly, we observed more amyloid deposition in the hippocampus of these mice compared to vehicle-treated APPswePS1ΔE9/nestin-δ-HSV-TK or APPswePS1ΔE9 mice. Taken together, these observations suggest the hypothesis that impaired hippocampal neurogenesis plays a key role in the development of cognitive deficits and neuropathology in AD, and that enhancement of neurogenesis would restore these deficits. Experiments will determine the effect of loss or gain of neurogenesis in FAD mice on extent of proliferation, survival and cell fate determination of hippocampal neural progenitor cells and new neurons (Specific Aim 1), progression of neuropathology (Specific Aim 2) and learning and memory (Specific Aim 3). In Specific Aim 4 we will examine the association between extent of neurogenesis, level of cognitive function and neuropathology in human brain tissue of Mild Cognitive Impairment (MCI) and AD patients. These experiments will determine the role of neurogenesis in AD and lead to the development of neurogenesis-based treatment of cognitive deficits in the disease.