Harnessing mRNA translation to increase the neuroprotective potential of disease-associated microglia in neurodegenerative diseases

Project Overview

Microglia are the brain’s immune cells. Research in recent years has revealed their crucial role in preventing the development of neurodegenerative diseases, including Alzheimer’s Disease (AD). However, the precise mechanisms by which microglia lose their potency in protecting the brain, enabling the development of AD, are not fully understood. Our research indicates that microglia dysfunction is related to molecular mechanisms responsible for the control of mRNA translation, the key step translating the genetic information stored in the genome to the production of proteins in the cell. Specifically, we discovered how overactivity of 4E-BPs, a family of proteins responsible for repressing mRNA translation, is contributing to this microglia dysfunction and AD progression. Increased levels of 4E-BP in the cerebrospinal fluid of AD patients correlate with more severe symptoms and we showed that genetically depleting 4E-BPs restores the normal function of the microglia cells both in a cell culture and a mouse model. Our goal in this project is to elucidate the molecular mechanisms by which mRNA translation impacts microglial function. By employing state-of-the-art CRISPR screen and other single-cell multiomic technologies we have developed to study biological functions at a single-cell resolution, we seek to identify and target specific mRNA regulators that could restore microglial function and health. The goal is to develop new therapeutic strategies that can halt or even reverse the progression of AD via mechanisms which restore the protective functions of the brain’s immune system. By understanding and manipulating the intricate molecular pathways that control microglia cells, this research could pave the way for significant advancements in AD therapy, opening new avenues to combat AD and similar neurodegenerative diseases.

Partners and Donors

Brain Canada, Weizmann Canada, and the Weizmann Institute of Science