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2022 Alzheimer's Association Research Fellowship (AARF)

From Space to Memory Under Pathological Tau

How may the spread of tau impact brain function in the earliest stages of Alzheimer’s?

James Carmichael, Ph.D.
Douglas Hospital Research Centre
Montreal, Canada


Tau is a protein that helps to maintain the structure of brain cells. In Alzheimer’s and 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 connecting abnormal tau and changes in an individual's cognition (such as memory, thinking and reasoning) remain unclear. 

Research suggests that abnormal tau begins to develop in the entorhinal cortex (EC), a brain region that functions as a center for the formation of memories and object recognition, among other tasks. Additionally, in studies of genetically engineered Alzheimer’s-like mice, scientists found that abnormal tau begins to spread by moving from the entorhinal cortex to another brain region impacted early in Alzheimer’s called the subiculum.  The subiculum helps control navigation and spatial memory (the ability to navigate around an environment), and the mice developed losses in their ability to navigate through an environment. Such findings suggest that similar changes may also occur in humans during the earliest stages of Alzheimer’s. 

Research Plan

Dr. James Carmichael and colleagues will study how the early spread of abnormal tau impacts navigation and memory in genetically engineered Alzheimer’s-like mice. First, the researchers will use a modified virus (called an adenoid-associated virus) to deliver abnormal human tau into the entorhinal cortex of the mice, where the first changes in tau build up in humans is detected. They will then administer tests of spatial memory to assess how the spread of abnormal tau from the EC to the subiculum may impact their navigating ability and other forms of memory. Next, the investigators will monitor how activity in the subiculum of the mice may be altered by the spread of abnormal tau, and how these changes may relate to their loss of memory and spatial awareness. Lastly, Dr. Carmichael’s team will use a novel electrical stimulation technique to reduce the spread of abnormal tau and possibly restore the rodents’ navigation and memory.   


If successful, this project could shed new light on how abnormal tau leads to brain changes in the earliest stages of Alzheimer’s. Such knowledge could lead to novel methods of early detection and treatment.

This Project has been made possible by the Canada Brain Research Fund (CBRF), an innovative arrangement between the Government of Canada (through Health Canada) and Brain Canada Foundation, and of the Alzheimer’s Association.

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