The Role of DYRK1A in Altered Microglia Biology in a Cellular Model of Alzheimer’s Disease in Down Syndrome

About the Research Project
Program
Award Type
Standard
Award Amount
$300,000
Active Dates
January 01, 2025 - December 31, 2027
Grant ID
A2024040S
Co-Principal Investigator(s)
Selina Wray, PhD, University College London (UK)
Goals
To determine if targeting DYRK1A kinase can normalized Alzheimer’s disease-related changes in microglia.
Summary
Down syndrome is a genetic condition, caused by an extra copy of chromosome 21, and is associated with a greatly increased risk of developing early-onset dementia caused by Alzheimer’s disease. Recent research has demonstrated the brain’s immune response to Alzheimer’s disease pathology differs in people who have Down syndrome and that this may contribute to the development of dementia. Our data indicate that the chromosome 21 gene, DYRK1A may contribute to this; here we propose to test this hypothesis in a new cellular model of Alzheimer’s disease in the context of trisomy of chromosome 21.
Unique and Innovative
We have identified a new target for AD-relevant microglia changes by a data-driven approach, using innovative transcriptomic methods and a unique dataset (Down syndrome AD). We will test if a novel DYRK1A kinase inhibitor, developed for the treatment of Down syndrome cognitive differences, is also useful for the treatment of AD microglia changes. This will be combined with cutting-edge phospho-proteomic methods to identify the kinase targets, providing novel insight into the regulation of microglia cell-states in the context of disease.
Foreseeable Benefits
This project will determine if the new DYRK1A inhibitor Leucettinib-21 can normalize AD-associated changes in microglia cells. This will provide key information to determine if Leucettinib-21 is a candidate for the treatment of Alzheimer’s disease-neuroinflammation and thus may be a useful therapy to slow the development of dementia.
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