2023 Alzheimer’s Association Leveraging Model & Data Resources to Advance Alzheimer’s and Dementia Discovery Program (ALZDISCOVERY)
Linking Integrin Dysfunction with Tauopathy in a LOAD Model
How do proteins that normally enable cell construction become dysfunctional and promote Alzheimer’s?
Christine Dengler-Crish, Ph.D.
Northeast Ohio Medical University
Rootstown, OH - United States
Background
Tau is a protein that helps maintain the structure of brain cells. In Alzheimer’s and other brain diseases called tauopathies, the shape of tau protein becomes modified or “misfolded,” a change that may contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. Scientists, however, do not yet fully understand the biological mechanisms underlying tau’s role in brain disease.
The gene that provides instructions for making tau is called microtubule-associated protein tau, or MAPT. Studies show that a certain variation of MAPT (called H1) may increase an individual's risk of developing brain diseases like Alzheimer’s. In initial research Dr. Christine Dengler-Crish and colleagues examined mice engineered to develop high levels of MAPT H1 and disease-related tau. They found that these animals also developed high levels of a type of integrin protein called avβ1. Integrin proteins normally help bind cells together, and avβ integrins help with nerve cell development and nerve cell-to-nerve cell communication in the brain. When avβ integrins become dysfunctional, however, they may promote a variety of dementia-related brain changes, such as inflammation and the spread of tau tangles. Dr. Dengler-Crish’s findings suggest that MAPT H1 may alter avβ1 activity in ways that lead to misfolded tau) and dementia.
Research Plan
Dr. Dengler-Crish and team will work to assess the links between MAPT H1, integrin dysfunction and tauopathy in late-onset Alzheimer’s (or LOAD, the most common form of Alzheimer’s). First, they will study mice with and without MAPT H1 to determine more precisely how this protein variation impacts the levels and activity of avβ integrins in the brain. Next, they will examine the molecular processes that underlie the role of MAPT H1 in integrin-related tau disease, brain inflammation and other brain changes of Alzheimer’s.
Impact
The results of this study could shed new light on the genetic factors that lead to tau clumping in dementia. This could also lead to novel dementia therapies that target avβ integrins.