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Memory depends on the ability of neurons to strengthen their connections through a process called long-term potentiation (LTP). In Alzheimer’s disease, this strengthening often fails, leading to synaptic dysfunction and contributing to cognitive decline. One candidate driver of this phenomenon is a chemical “tag” on RNA known as m6A. This modification helps control which messenger RNAs are translated into proteins during the rapid, local bursts of protein synthesis that drive LTP. Importantly, m6A patterns are altered in Alzheimer’s, but no current method can directly show how changes at specific sites alters protein production from these messenger RNA.

This project will develop a sequencing technology that, for the first time, can read both the m6A status of an RNA molecule and how many ribosomes are translating it, giving a direct measure of how modifications shape protein synthesis. We will apply this tool to human neurons carrying Alzheimer’s associated mutations as well as matched healthy neurons, before and after chemically inducing LTP. This will allow us to pinpoint the exact m6A sites where disease-specific changes disrupt protein production required for synaptic strengthening. Finally, we will test whether targeted “editing” of these sites can restore neuronal function. 

Using CRISPR-based molecular tools, we will selectively remove m6A from candidate RNAs and then measure whether this rescues the neurons’ ability to undergo LTP.By combining method development, disease application, and functional testing, this project delivers both a powerful new platform for linking RNA modifications to protein synthesis and a proof-of-concept for reversing pathological changes in Alzheimer’s. Even if individual site editing does not restore memory-related function, the technology and dataset will provide a lasting resource for understanding how RNA chemistry shapes brain health and disease.