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2021 Alzheimer's Association Research Grant (AARG)

A Novel Role for APP in Brain Circuit Function: Implications for AD Therapy

What is the role of the parent protein of beta-amyloid in brain cell network and activity in Alzheimer’s?

Marc Aurel Busche, M.D., Ph.D.
University College London
London, United Kingdom


Amyloid precursor protein (APP) is the parent molecule of beta-amyloid, that accumulates to form plaques, a hallmark brain change observed in Alzheimer’s. Scientists have long studied the impact of APP and beta-amyloid in Alzheimer’s, yet relatively little is known about the normal functions of APP and two APP-like proteins called APLP1 and APLP2.  

In preliminary work, Dr. Marc Aurel Busche and colleagues have studied a novel mouse model genetically engineered to lack all three APP “family” proteins. The researchers found that the nerve cells in these mice may become less active and may be less able to communicate with one another – especially between distant brain regions. Other studies have found dysfunction in nerve cell activity in early Alzheimer’s. Based on their preliminary results, Dr. Busche believes that APP proteins may be associated with impacting nerve cell dysfunction in early Alzheimer’s. 

Research Plan

Building on their earlier findings, Dr. Busche and colleagues will conduct further studies with their genetically engineered mouse model and with mouse nerve cells in a laboratory dish. Using cutting-edge scanning technology, they will study more precisely how the loss of APP may impact activity levels in different types of nerve cells and broader nerve cell networks between different brain regions. The researchers will then study the biological mechanisms that may underlie the potential links between APP proteins and nerve cell function and how these associations may impact behavior in the mice.


Dr. Busche’s effort could help us better understand the normal function of APP in the brain cell activity and how loss of APP may impact early brain changes observed in Alzheimer’s.  If successful, the findings may ultimately give rise potential therapeutic targets for preventing Alzheimer’s or tackling brain changes in early stages of Alzheimer’s.

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