Neuronal mechanisms of altered circuit excitability in early Alzheimer's

到2050年，预计将有1400万美国人患有痴呆症。阿尔茨海默病（AD）是一种 最常见的痴呆症，占所有病例的70%。阿尔茨海默氏症的一个标志性特征 疾病（AD）是进行性突触和神经元病理学-最终导致认知障碍的因素。 下降虽然有越来越多的信心，特定的生物标志物可以预测AD的发生， 在个体中，导致疾病发生的分子和细胞机制仍然存在 不太了解。如果我们希望阻止这种现象， 足够早地发生神经退化以保存记忆和认知。有趣的是， 这种现象现在已经在患有轻度认知障碍的人以及患有轻度认知障碍的人中观察到。 AD早期动物模型。这些观察结果一致认为，神经元回路受 AD在疾病的早期阶段变得更加活跃。此外，有证据表明， 过度活跃的神经元变得易受突触退化的影响-这是AD的标志性特征。我们的目标 是揭示导致这种早期回路功能障碍的神经机制。证据表明 抑制性中间神经元在早期AD期间易受活性变化的影响。例如action 在前驱AD小鼠中，中间神经元的电位（AP）放电发生改变，但在其他细胞类型中的改变较少 模型中间神经元中的AP放电由一个独特的离子通道子集控制， 表明AD期间中间神经元中特定离子通道的表达发生变化。然而，在这方面， 离子通道的表达、亚细胞运输或生物物理特性发生了什么变化， 早期AD仍不清楚。使用人类APP表达小鼠模型和尖端分子， 电生理学和双光子成像技术，我们建议揭示特定离子的变化， 这些GABA能中间神经元中的通道。根据我们的初步数据，我们假设， 在中间神经元中的特定类别的Kv通道的修饰直接有助于皮质神经元的神经传导。 早期AD的过度兴奋。重要的是，研究将在疾病早期离体进行 过程（即，在斑块形成或突触丧失之前）。这项提案的结果将有助于我们更好地 了解早期AD期间电路病理的起始因素，并可能直接导致 开发分子和细胞疗法，阻止突触和神经元病理学。

14 million Americans are projected to be living with dementia by 2050. Alzheimer’s disease (AD) is the most common form of dementia, responsible for ~70% of all cases. A hallmark feature of Alzheimer’s disease (AD) is progressive synaptic and neuronal pathology- factors that ultimately result in cognitive decline. While there is increasing confidence that specific biomarkers can predict the occurrence of AD in individuals, the molecular and cellular mechanisms contributing to the initiation of the disease remain poorly understood. Gaining a greater understanding of these mechanisms is crucial if we hope to halt neurodegeneration early enough to preserve memory and cognition. Interestingly, a common phenomenon has now been observed in both humans with mild cognitive impairment, as well as in animal models during the early stages of AD. These observations agree that neuronal circuits affected by AD become more active during the early stages of the disease. In addition, evidence exists that hyperactive neurons become vulnerable to synaptic degradation- a hallmark feature of AD. Our objective is to uncover neuronal mechanisms that result in this early-stage circuit dysfunction. Evidence exists that inhibitory interneurons are vulnerable to changes in activity during early AD. For example, action potential (AP) firing is modified in interneurons, but less so in other cell types, in prodromic AD mouse models. AP firing in interneurons is controlled by a unique subset of ion channels, and it has been suggested that the expression of particular ion channels change in interneurons during AD. However, what changes in the expression, subcellular trafficking, or biophysical properties of ion channels occur in early AD remain unclear. Using human APP-expressing mouse models and cutting-edge molecular, electrophysiological, and 2-photon imaging techniques, we propose to uncover changes in specific ion channels in these GABAergic interneurons in depth. Based on our preliminary data, we hypothesize that modification of a particular class of Kv channels in interneurons directly contributes to cortical hyperexcitability in early AD. Importantly, studies will be performed ex vivo early on in the disease process (i.e., before plaque formation or synapse loss). Findings from this proposal will help us better understand the initiating factors of circuit pathology during early AD and could lead directly to the development of molecular and cellular therapies that halt synaptic and neuronal pathology.