2024 Alzheimer's Association Research Grant (AARG)
Impaired Microglial Modulation of Neuronal Function in Alzheimer’s Disease
How may a protein on the surface of immune cells in the brain become altered and promote nerve cell dysfunction in Alzheimer’s?
Keran Ma, Ph.D.
University of Texas Health Science Center at Houston
Houston, TX - United States
Background
During the development and progression of Alzheimer’s, complex changes occur in the structure of the brain and brain activity. Studies show that Alzheimer’s-related brain changes may occur across wide-scale “networks” of brain cells — networks that include multiple brain regions and control different types of memory and other cognitive functions. Within these networks, nerve cells in the brain use electrical signals to communicate with one another and with other cells, including microglia (the brain’s principal immune cells). Such communication is essential for brain function, including learning and memory.
Increasing evidence suggests that communication between nerve cells and microglia become altered in Alzheimer’s, which may contribute to changes in brain function associated with the disease. Such alterations may be related to a protein on the surface of microglia called Triggering Receptor Expressed in Myeloid cells 2 (TREM2). In preliminary research with genetically engineered mice, Dr. Keran Ma and colleagues found that a particular variation in TREM2 (called TREM2 R47H) may prevent microglia from responding properly to nerve cell signals, a problem that may lead to abnormal brain network activity and dementia-related cognitive impairment.
Research Plan
Dr. Ma and the team will now conduct a larger study to clarify how TREM2 R47H impacts microglial function and cognitive decline. First, they will analyze mice that have been engineered to express the TREM2 variation. Such analysis will involve examining whether microglia lose their ability to respond properly to certain neurotransmitters (chemical messengers) sent by nerve cells, and whether this loss of function may be related to changes in rhythms produced by nerve cells (rhythms known as gamma oscillations). They will also assess how these changes impact activity among individual nerve cells and across nerve cell networks. Lastly, the researchers will develop another mouse model that both develops Alzheimer’s-like brain changes and expresses TREM2 R47H. They will study how possession of the protein variation may relate to beta-amyloid clumping and other hallmark brain changes in Alzheimer’s disease.
Impact
Dr. Ma’s study could help clarify the role of microglia in dementia. It could also identify a microglial protein as a target for novel dementia therapies.