2019 Alzheimer's Association Research Grant (AARG)

TAK1 as a target of Alzheimer’s disease

Does blocking a protein associated with brain inflammation reduce brain changes seen in Alzheimer’s?
 

Jun Ninomiya-Tsuji, Ph.D.
North Carolina State University
Raleigh, NC - United States

Background

Studies indicate that brain inflammation may help initiate or further the progression of Alzheimer’s. Some recent studies have shown that reducing inflammation in the brain’s support cells, (called glial cells which is one of the largest population of brain cells), in genetically engineered Alzheimer’s-like mice slows disease progression. Understanding the impact of reducing inflammation in nerve cells is complex and has many unanswered questions.
 
Studies suggest that a protein TAK1 plays a key role in the brain’s inflammatory response, and higher than normal levels of TAK1 activity have previously been reported in the brains of people with Alzheimer’s. In preliminary studies, Dr. Jun Ninomiya-Tsuji discovered that levels of TAK1 activity are also higher in the brains of genetically engineered Alzheimer’s-like mice and that blocking the function of TAK1 in mice reduces the brain changes seen in these mice. Based on these findings, Dr. Ninomiya-Tsuji believes that it is important to further study the impact of blocking TAK1 activity in Alzheimer’s.
 

Research Plan

Dr. Ninomiya-Tsuji and her colleagues will use two kinds of genetically engineered Alzheimer’s-like mice- one that has amyloid plaques and other that has tau tangles in their brains; both amyloid plaques and tau tangles are hallmarks of Alzheimer’s.  In these mice, the researchers will delete the gene that provides the instructions for making the TAK1 protein in either: nerve cells or nerve cells and glial cells. Dr. Ninomiya-Tsuji will then compare the levels of beta-amyloid and tau proteins in these Alzheimer’s-like mice to levels in cognitively unimpaired mice.
 
Furthermore, the researchers will also give both kinds of Alzheimer’s-like mice and cognitively unimpaired mice, two drugs that block the function of the TAK1 protein. Dr. Ninomiya-Tsuji and her team will then compare the accumulation of beta-amyloid plaques and tau tangles in their brains and evaluate the impact of these drugs.
 

Impact

The study results could identify a novel therapeutic target to prevent or reduce brain inflammation in Alzheimer’s. If successful, the drug that blocks TAK1 activity could be further tested as a potential treatment for Alzheimer’s in human clinical studies.