Astrocytic NLRX1 Contributes to Multiple Aspects of Alzheimer's Disease

This project aims to define how the protein NLRX1 in astrocytes drives Alzheimer’s disease progression and identify the mechanisms by which targeting it could preserve neuronal resilience, growth, and cognitive function.

Alzheimer’s disease is the leading cause of dementia, marked by memory loss and brain cell dysfunction. Astrocytes, supportive brain cells, influence disease progression. We’re studying the role of NLRX1 in astrocyte mitochondria that regulates metabolism and supports neuronal health. Our data suggest NLRX1 worsens Alzheimer’s by promoting harmful protein buildup and cognitive decline. Removing NLRX1 in astrocytes may boost their protective functions, reduce toxic signals, and support neurons. This work could reveal new therapeutic targets to slow or prevent Alzheimer’s disease.

This proposal is the first to investigate the role of NLRX1 in Alzheimer’s disease, representing a completely unexplored therapeutic target in neurodegeneration. A key innovation is the use of novel astrocyte-specific NLRX1 knockout mice, which allow us to isolate the contribution of this protein in astrocytes alone rather than the whole brain, providing unprecedented cellular precision. Finally, by combining in vivo mouse models with proteomic screening of the astrocyte secretome, this project takes a multi-dimensional approach to understanding how astrocytes communicate with and support neurons in the context of Alzheimer’s disease.

If successful, this work will establish NLRX1 as a novel therapeutic target in Alzheimer’s disease, opening new avenues for drug development aimed at modulating astrocyte activity to slow or prevent neurodegeneration. Beyond Alzheimer’s disease, the findings will shed light on fundamental principles of how astrocytes communicate with and support neurons, with broad implications for other neurodegenerative diseases such as Parkinson’s disease. Ultimately, a deeper understanding of how brain support cells contribute to cognitive decline could accelerate the development of treatments that preserve memory and quality of life for the millions of people affected by Alzheimer’s disease worldwide.