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

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.