Programmatic Activation of the Neurodegenerative TREM2 Pathway by TCIP1

Over six million Americans currently live with Alzheimer's disease, a number expected to rise to about 14 million
by 2060 as the population ages. Alzheimer’s is a major cause of dementia and the fifth-leading cause of death in
the U.S., so there is a growing need to address this disease. Microglia, the brain's immune cells, are crucial in
protecting brain health by clearing harmful substances and maintaining neural function. However, when microglia
are inactivated, inflammation can increase, worsening brain damage and accelerating Alzheimer's progression.
One key protein that helps activate and proliferate healthy microglia is TREM2. This protein is only expressed in
a category of immune cells called myeloid cells (including microglia) and is well-known in the field of
neurodegeneration as being protective and anti-inflammatory. Increasing TREM2 levels in microglia has shown
promising potential benefits for treating Alzheimer's. Unfortunately, few drugs effectively boost TREM2,
highlighting the urgent need for new therapeutics.

We have developed a drug in our lab that activates genes in a highly selective manner. This drug is called
Transcriptional/epigenetic Chemical Inducers of Proximity 1 (TCIP1) and effectively activates death genes in
cancerous lymphocytes (a type of immune cells in the blood), while sparing other cell types, including myeloid
cells. Excitingly, our preliminary data indicate that TCIP1 can also increase TREM2 levels in the mouse spleen by
24-fold, an organ with a variety of immune cells, including myeloid cells, suggesting its potential to activate
TREM2 in other myeloid cells, like brain microglia.

This proposal aims to identify the specific myeloid cells in which TCIP1 boosts TREM2, uncover the underlying
mechanisms of this massive induction, and confirm its effects on brain microglia. Success in this research could
lead to the development of a groundbreaking drug, offering new hope for millions of Alzheimer's patients
worldwide.