Plasticity and vulnerability of basal forebrain cholinergic neurons in Alzheimer's Disease

基底前脑胆碱能神经元的严重缺失是阿尔茨海默病的早期标志 (Ad)。由于胆碱能神经支配对认知是必不可少的，BFCNs的退化可能与智力有关 在AD患者中呈下降趋势。目前涉及胆碱能药物的AD疗法提供的益处不大，但并不是 根据发病机制，不能阻止BFCN退变。BFCN易受攻击的原因 阿尔茨海默病与细胞死亡的关系在很大程度上是未知的，但BFCN的丢失预示着皮质的退化，以及胆碱酯酶 抑制剂可以减少基底前脑、皮质和海马区的萎缩。这些观察结果支持 BFCNs保护能延缓AD发病的前提。因此，迫切需要确定 BFCNs细胞死亡的分子机制。在这个提案中，我们将研究相关的分子事件 伴有BFCN功能障碍。我们的重点是神经元过度兴奋，这是AD患者的一个突出的早期特征 与认知缺陷有关。过度活动诱导内稳态突触可塑性(HSP)，这是一种代偿性 调节突触强度以应对神经元活动扰动的机制，从而维持 在最佳范围内励磁，并保持网络稳定性。然而，人们对热休克蛋白知之甚少 哺乳动物中枢胆碱能突触，在正常情况下或在AD模型中。我们将检验这一假设 高兴奋和HSP机制加重了AD的发病。此外，我们建议BFCNs， 在AD早期是高度脆弱和受影响的，为检测这种功能障碍提供了灵敏的读数。 我们提出了以下目标：1)使用优化的隔区-海马区共培养系统，我们将检查 正常BFCN和胆碱能突触发育的过程；形态和功能的测定 在过度兴奋条件下胆碱能神经元和突触发生的变化；并利用从AD小鼠模型制备的类似的共培养方法来检查BFCNs在正常发育过程中的扰动。 对过度兴奋的反应，以及对不同形式的细胞死亡的敏感性。2)我们将分析BFCN和 用多学科方法检测体内海马神经元的动态平衡反应 过度兴奋，并使用Chat-Cre小鼠与AD小鼠模型杂交来识别BFCN的损害 结构或突触功能，在基础和过度兴奋条件下。这些重要的研究使用了 创新技术，研究具有基础性和翻译重要性的问题。如果成功，这些发现 可能导致改善治疗阿尔茨海默病BFCN神经变性的方法。

The profound loss of basal forebrain cholinergic neurons (BFCNs) is an early hallmark in Alzheimer’s disease (AD). As cholinergic innervation is essential for cognition, degeneration of BFCNs may be linked to mental decline in AD patients. Current AD therapies involving cholinergic drugs provide modest benefits but are not based on disease mechanisms and do not halt BFCN degeneration. The reasons for the vulnerability of BFCNs to cell death in AD are largely unknown, but BFCN loss predicts degeneration in cortex, and cholinesterase inhibitors reduce atrophy in basal forebrain as well as cortex and hippocampus. These observations support the premise that protection of BFCNs could slow pathogenesis in AD. Thus, there is an urgent need to identify molecular mechanisms of cell death in BFCNs. In this proposal, we will investigate molecular events associated with BFCN dysfunction. We focus on neuronal hyperexcitability, which is a prominent, early feature in AD patients linked to cognitive deficits. Hyperactivity induces homeostatic synaptic plasticity (HSP), a compensatory mechanism that tunes synaptic strength in response to perturbations in neuronal activity, thereby maintaining excitation within an optimal range and preserving network stability. However, little is known regarding HSP in mammalian CNS cholinergic synapses, in normal conditions or in AD models. We will test the hypothesis that hyperexcitation and HSP mechanisms exacerbate AD pathogenesis. Furthermore, we propose that BFCNs, which are highly vulnerable and affected early in AD, provide a sensitive readout for detecting such dysfunctions. We propose the following aims: 1) Using an optimized septal-hippocampal co-culture system, we will examine the course of normal BFCN and cholinergic synapse development; determine morphological and functional changes that occur in cholinergic neurons and synapses during overexcitation conditions; and utilize similar co-cultures prepared from an AD mouse model to examine the perturbations to BFCNs in their normal development, response to hyperexcitation, and susceptibility to distinct forms of cell death. 2) We will analyze BFCNs and target hippocampal neurons in vivo with multidisciplinary approaches to examine the homeostatic responses to hyperexcitation, and use ChAT-Cre mice crossed to an AD mouse model to identify impairments in BFCN structure or synaptic function, under both basal and hyperexcitation conditions. These significant studies use innovative technology to investigate questions of basic and translational importance. If successful, the findings may lead to improved therapies against BFCN neurodegeneration in AD.