2021 Alzheimer's Association Research Grant (AARG)

Establishing the Role of PERK Activation on the Progression of Tauopathy

What are the biological contributors to abnormal accumulation of tau protein in the brain in Alzheimer’s and other dementias?

Jose Abisambra, Ph.D.
University of Florida
Gainesville, FL - United States

Background

The protein tau helps maintain the structure of brain cells. In Alzheimer’s, other brain diseases 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. However, the mechanisms linking abnormal tau build up and changes in a person’s cognition (such as memory, thinking and reasoning) remain unclear. 

The buildup of the tau protein in Alzheimer’s and other brain diseases may impact other biological processes in the cell, such as the production of other proteins.  A structure called the endoplasmic reticulum serve as the protein-making “factories”.  The buildup of the tau protein in Alzheimer’s and other brain diseases may impact other biological processes in the cell, such as the production of other proteins.  A structure called the endoplasmic reticulum serve as the protein-making “factories”. Recent studies suggest that stress in the endoplasmic reticulum of brain cells caused by a specific biological process known as the unfolded protein response may play a role in tau accumulation. 

Dr. Jose Abisambra and colleagues have shown that increasing the activity of that increasing the activity of specific proteins in the endoplasmic reticulum may also reduce the levels of tau in the brain of genetically engineered mice. One of these proteins known as PERK, which is endoplasmic reticulum stress protein and reduces levels of tau in the brain of genetically engineered Alzheimer’s-like mice. However, it is unknown how PERK works to reduce tau and if this will result in cognitive benefits.

Research Plan

Dr. Abisambra and his team believe that PERK may reduce abnormal tau accumulation and improve cognition by activating the adaptive unfolded protein response. 

In this study, the research team will investigate the mechanisms that PERK may act to reduce tau build up. They will use genetically engineered Alzheimer’s-like mice, as well as in brain cells from mice that have been genetically engineered to have reduced PERK levels, to better understand these biological mechanisms. In addition, Dr. Abisambra and colleagues will also study how changing the levels of PERK in these models may impact the tau build up and affect changes in cognition.
 

Impact

This project may lead to a better understanding of how and why abnormal tau accumulation in the brain contributes to cognitive decline. The results may identify potential new opportunities to develop therapies involved in the increase of protein response that contribute to abnormal tau accumulation in Alzheimer’s and other dementias.