Revealing Early Biomarkers in Alzheimer’s Disease

Project Summary

Aim #1 will identify changes at the RNA level of specific genes in cell types in the hippocampus. In aim #2 we will link RNA changes to changes at the protein level focusing on synaptic changes. In aim #3 we will link the molecular and synaptic changes to physiology using the common spatial map. These data will enable the construction of a novel model that explains the functional consequences of early molecular events in Alzheimer’s disease. 

Here, we will use a new spatial, super-resolved, and multiplexed approach, which allows probing hundreds of gene targets in situ with synaptic resolution. Our approach allows the correlation of RNA molecules, synapse morphology, and function to one another and to proximity to plaques. This unique analysis will be performed at the early stages of AD, allowing early identification of AD-associated biomarkers. We will use, first time in AD, a novel platform we developed, to detect molecular changes of hundreds of genes in intact brain tissues at early disease stages, and relate them to specific cell types, proximity to amyloid deposits, and sex differences. This work will answer long-standing and critical questions: What are the mechanisms that lead to a synaptic loss? Which cells are involved? Do amyloid plaques intensify it? Understanding these mechanisms will help develop early diagnostic and therapeutic tools that can prevent synaptic loss and hinder AD progression.