Mapping AD Memory Failure: Molecules to Connectivity of Brain Network

 描述（由申请人提供）：阿尔茨海默病（AD）痴呆症目前困扰着美国超过500万人，预计到2020年将增加到1100万至1600万老年人 2050年。最近，我和我的同事证明了衰老和AD小鼠模型中的空间记忆缺陷与海马神经元兴奋性的降低相对应。然而，这些内在变化的分子介质和兴奋性变化的后果，在个别神经元水平上，一旦它们被嵌入到一个活跃的神经网络仍然是未知的。目前的建议是基于我们的新的初步数据显示，在AD小鼠模型中的记忆缺陷对应于兴奋性和抑制性受体的特定子集的表达的变化。这些表达的变化表明海马神经网络的兴奋性和抑制性影响的平衡发生了变化。一个适当的平衡已被证明是至关重要的生成正常的伽马带振荡网络活动和长期同步的β和γ振荡。我们有新的电生理试验数据，表明我们的AD小鼠模型中的空间记忆缺陷与海马（Hip）和前额叶皮层（PFC）振荡网络活动在β和γ频率范围内的一致性显著降低相关。关于受体表达的其他初步数据为观察到的Hip-PFC一致性降低提供了可能的机制解释。据推测，通常需要记忆（通过从头合成）和可塑性，或Hip-PFC网络的连贯性功能障碍，或两者的质膜蛋白的失调，在AD的空间记忆缺陷的基础，将在随后的目标进行测试。拟议研究的结果有可能对识别AD相关记忆障碍的新治疗方法产生重大影响。我们的分子和网络水平的分析也可能发现生物标志物，可用于提前检测阿尔茨海默病的潜在发作，以便治疗可以更早地开始，成功率更高。

 DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) dementia currently afflicts over 5 million people in the United States and is projected to rise to 11-16 million elderly by the year 2050. Recently my colleagues and I demonstrated that spatial memory deficits in mouse models of aging and AD correspond to a decrease in excitability of neurons of the hippocampus. However, the molecular mediators of these intrinsic changes and the consequence of excitability changes at the individual neuron level once they are embedded into an active neural network remains unknown. The present proposal is based on our new preliminary data showing that memory deficits in an AD mouse model correspond to changes in the expression of a specific subset of excitatory and inhibitory receptors. These changes in expression are indicative of a shift in the balance of excitatory and inhibitory influences on hippocampal neural networks. An appropriate balance has been shown to be crucial for the generation normal gamma band oscillatory network activity and for the long range synchronization of beta and gamma oscillations. We have new electrophysiological pilot data, showing that spatial memory deficits in our AD mouse model is correlated with a significantly reduced coherence of hippocampus (Hip) and prefrontal cortical (PFC) oscillatory network activity in the beta and gamma frequency ranges. Additional preliminary data on receptor expression provide a probable mechanistic explanation for the observed reduction in Hip-PFC coherence. It is posited that either misregulation of plasma membrane proteins normally required for memory (via de novo synthesis) and plasticity, or the dysfunction of Hip-PFC network coherence, or both, underlie spatial memory deficits in AD that will be tested in ensuing aims. Outcomes of the proposed research have the potential to make a major impact on the identification of new treatments for AD-related memory disorders. Our molecular and network level analysis may also discover biomarkers that could be used to detect potential onset of Alzheimer's disease well in advance, so that treatment could begin earlier with better success rates.