Compelling evidence has suggested that mitochondrial dysfunction is an early event in Alzheimer?s Disease (AD) pathophysiology. This mitochondrial dysfunction is closely related to the elevated level of intracellular A?, which appears to be accumulated within mitochondria in the brains of both Alzheimer?s patients and mouse models. How mitochondria actively accumulate A? is not clear, and thus represents a large gap of knowledge in the field.
We aim to understand the very first step of this accumulation process by studying the detailed molecular mechanism of substrate/receptor interaction. We have identified that A? is recognized by a non-canonical receptor, Tom22, within the mitochondrial protein import machinery. In this proposal, we expect to perform two related but independent specific aims to reach that goal. 1). We will characterize the interaction between A? and Tom22 receptor in details, by biophysical, biochemical and cell biology tools; 2). We expect to determine three dimensional atomic structures of Tom22 and Tom22/A? complex. The functional and structural information gained here are expected to reveal detailed molecular mechanism underlining the detrimental process of mitochondrial uptake of A? peptides, and thus provide novel models to screen molecules that are capable of disrupting the specific Tom22/A? interaction. Thus, the outcome of this proposal is expected to have important positive impact in treating mitochondrial dysfunction caused by A? in AD.
Mitochondrial dysfunction caused by amyloid beta peptides is a common symptom in the pathogenesis of the Alzheimer?s Disease. We aim to understand the molecular mechanism underlining the detrimental process of mitochondrial accumulation of amyloid beta. We anticipate that the knowledge gained here by completing the proposal will substantially move the field forward and be used for future drug development.
