Blocking Jumping Genes to Stop Brain Inflammation in Alzheimer's Disease

The goal of this project is to determine if blocking the retrotransposon LINE-1 can prevent sterile inflammation in human Alzheimer’s disease neurons.

Alzheimer’s disease (AD) is a fatal neurodegenerative disease with no available cures. By generating patient-specific induced neurons (iNs), we found that there is a small population of inflammatory neurons that could be targeted to treat AD instead of strategies that affect the entire brain. However, how these neurons become inflammatory, and therefore, ways to intervene, are currently unknown. In this project, we deeply characterize a promising genetic target driving inflammation and assess if blocking its activity is a candidate for reversing hallmarks of AD.

Transdifferentiation of iNs maintaining an aged profile represents a technical innovation that dramatically improves the relevance of in vitro models for studying AD. This proposal capitalizes on this technical innovation to collect long-read single-cell RNAseq data from age-relevant human AD neurons for the first time. Our experiments are conceptually innovative because they focus on a novel source of cytoplasmic DNA in AD neurons that could have wide-ranging implications for neuroinflammation and identify novel treatment avenues for preventing non-self DNA sensing in aged human neurons.

The research field will benefit from the production of a novel long-read expression dataset in aged human neurons that can be used to discover repetitive element activity and novel splice isoform changes that impact human biology late in life. It will also increase our mechanistic understanding of LINE-1 activity by monitoring its location, a hotly debated topic, and the ability of existing drugs to modify LINE-1 activity in neurons. The general public will benefit from further insight into the role of LINE-1 in aging pathologies and directly test the intervention’s safety and efficacy.