This proposal seeks to solve a vital problem: how can Alzheimer?s disease (AD) related changes be identified early in disease so that pathology can be prevented? To address this problem, we focus on a key subcellular structure, the synapse. Synapses are excellent targets because: 1) their integrity is central to cognitive function, 2) they are sensitized to dysfunction by aging, and 3) they are affected early in AD and causal to cognitive decline. In particular, work by our group and others implicates an ancient immune modulator called complement in AD synaptic pathogenesis. However, it has been difficult to study complement mediated synaptic decline because synapses themselves are small and heterogeneous. To overcome these limitations, we have developed the retina as a system to dissect synaptic biomarkers in AD. Unlike the brain, the retina is well mapped, accessible, and genetically tractable even at the level of single synapses. Moreover, the retina is the site of clinically relevant AD pathology, and it can be assayed noninvasively over time. Using this system, we will identify complement driven changes in the molecular, synaptic, and functional properties of the retina to serve as preclinical biomarkers for AD progression. To achieve this, we have developed novel tools and approaches: 3D nanoscopic imaging, cell-specific sequencing that maintains spatial tissue information, and paired functional analysis of the retina and the brain. These studies will provide unparalleled insights into the structural and molecular regulators of synaptic integrity in AD. They will also lead to the identification of novel biomarkers for detecting AD progression that may ultimately be useful in preventing AD development.
Alzheimer?s disease affects millions of individuals and can progress for decades before it is diagosed. In part, this is because we lack good biomarkers for early disease that can be measured in an accesable region of the nervous system. To solve this problem, we focus our analysis on the retina, a well mapped and approachable CNS circuit, and the syanpses within it. Syanpses represent the relay points between neurons, and their degeneration is thought to underlie progessive cogntive decline in AD. In this study, we use new tools aimed at understanding how and why syanpses degrade and identify biomarkers for their decline. These approaches will open up new theraputic avenues for halting AD progression and improving public health.