2024 Alzheimer's Association Research Fellowship (AARF)
Understanding the Role of the Complement Pathway in Alzheimer's Disease
How does an immune pathway impact the accumulation and movement of tau protein in the brain?
Naoto Watamura, Ph.D.
University College London UK Dementia Research Institute
London, United Kingdom
Background
Tau is a protein that helps support nerve cell structure and transport nutrients within the cell. In Alzheimer’s and other brain diseases called tauopathies, the shape of tau protein becomes modified or “misfolded,” a change that may contribute to the accumulation of tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. Studies show that abnormal tau protein can move from one nerve cell to another, possibly contributing to the progression of brain changes associated with these diseases. However, the biological mechanisms behind how tau accumulates and moves through the brain are not fully understood.
The immune system is complex and serves to maintain our overall health. The complement system is part of the immune system and is made up of proteins that clear waste and promote inflammatory responses to help fight infection. Recent studies suggest that activation of the complement system, and subsequent inflammation, may contribute to brain changes associated with cognitive impairment in Alzheimer’s. Dr. Naoto Watamura and colleagues believe that activation of a specific complement protein, called C1q, may impact microglia, the brain’s primary immune cells, and involve them in the movement of tau between brain cells.
Research Plan
Dr. Watamura and the team have developed genetically engineered Alzheimer’s-like mice to study how abnormal tau may be associated with activation of the complement system. First, the researchers will perform RNA sequencing on microglia from the mice to determine the gene activity associated with abnormal tau. They will investigate changes in the complement system in microglia that surround areas of abnormal tau accumulation. Next, the team will study how removing C1q impacts tau accumulation and the density of synapses (specialized areas between cells that allow them to communicate) in their mouse models. They will determine if C1q deficiency impacts the activity of microglia and the movement of tau between brain cells. Finally, Dr. Watamura and colleagues will inject tau into the brains of their genetically engineered mice and subsequently examine their brains to study how C1q deficiency may impact the rate at which abnormal tau moves from cell to cell.
Impact
This study may shed light on how abnormal tau accumulates and spreads in the brains of individuals with different neurodegenerative diseases, including Alzheimer’s. The findings may support the development of novel therapeutic approaches to prevent or slow the spread of abnormal tau.