Neuropathology of synapses in AD and ADRD - PROJECT SUMMARY / ABSTRACT Although its molecular mechanisms remain to be clarified, the anatomic basis of cognitive impairment in Alzheimer's disease (AD) is injury and degeneration of synapses. Subpopulations of neurons in different brain areas may be more or less susceptible to specific types such insults Yet, molecular characterization of synapses in AD and AD–related dementias (ADRD) is limited, leaving the factors underlying this selectivity and the fidelity of widely-used mouse models to the human condition unclear. Here, we propose to fill these important gaps in selective cell vulnerability in aging and AD by identifying molecular signatures to suggest or confirm cellular pathways that may mediate vulnerability. The proposed project will accomplish this using a unique tissue resource and novel technology developed by us, and couple them with cutting-edge machine learning (ML) techniques to enhance differential signals and achieve deeper insights into the factors underlying selective neuron vulnerability or resilience. The novel technology that we have developed is called Synaptometry by Time-of-Flight, or SynTOF, and it provides an unparalleled opportunity for multiplex molecular analysis of millions of single synaptic events. We will build on our preliminary data, which coupled this new technology with ML approaches to gain novel insights into synaptic injury in AD, including in a transgenic mouse model that regionally overexpresses amyloid (A) β peptides in neurons, and which highlight the value of SynTOF in discovering the molecular patterns of injury in human synaptic subtypes, as well as assessing the fidelity of mouse models at the single synaptic level. Drawing on our unique tissue resource of cryopreserved synaptic preparations from participants with extensive clinical, genetic, and neuropathologic annotation, novel and powerful technology, and robust computational approaches, we propose to test the hypothesis that synapse injury in AD and ADRD is disease-, brain region-, and synapse subtype-specific, thereby highlighting new targets for therapeutic intervention and determining the extent to which three commonly used transgenic mouse lines model the synaptic injury of humans. When successfully completed, our novel resources and approach will provide unique insights into pre- and postsynapse subtype-specific mechanisms of injury at unprecedented scale, and further highlight new therapeutic targets for AD and ADRD.
