Mapping and Manipulating Cholingeric Basal Forebrain Activity in a Mouse Model of Alzheimer's Disease

项目总结 阿尔茨海默病(AD)是最常见的痴呆症形式，在美国约有580万人受到影响 美国。AD的主要药物干预，如乙酰胆碱酯酶抑制剂和NMDA 受体拮抗剂能够暂时改善认知功能，但目前还没有治疗方法 停止或逆转AD进展。AD患者的几个组织病理学特征，包括形成 细胞外Aβ斑块、神经原纤维缠结和基底前脑胆碱能加速变性 神经元(BFCNs)。这种明显的BFCN变性被认为是认知功能障碍的主要潜在原因 人类阿尔茨海默病患者在疾病发展过程中观察到的缺陷。这份补充申请建议 利用通过目前正在进行的研究获得的工具和信息，父母奖是“遗传的” 解剖胆碱能信号在体重控制中的作用“(R01DK109934)，其中我们选择性地 用于遗传操作和生物学分析的基底前脑胆碱能神经元，以阐明其 参与阿尔茨海默病。我们将具体调查BFCN是否因其损失而导致AD进展，或者 为潜在的神经保护途径提供激活。

PROJECT SUMMARY Alzheimer’s Disease (AD) is the most common form of dementia, affecting roughly 5.8 million people in the United States. Primary pharmaceutical interventions for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonists, are capable of temporarily improving cognitive function, but no current treatments exist to halt or reverse AD progression. Several histopathological hallmarks manifest in AD patients, including formation of extracellular Aβ plaques, neurofibrillary tangles, and accelerated degeneration of basal forebrain cholinergic neurons (BFCNs). This marked BFCN degeneration is believed to be a major underlying cause of the cognitive deficits observed in human AD patients throughout disease progression. This supplemental application proposes to utilize tools and information garnered through current research being conducted the parent award “Genetically dissecting cholinergic signaling in body weight control” (R01DK109934), where we have selectively targeted basal forebrain cholinergic neurons for genetic manipulations and biological analysis, to elucidate either their involvement in AD. We will specifically investigate if BFCNs contribute to AD progression with their loss, or provide potential neuroprotective avenues with activation.