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Can studying different subtypes of Alzheimer’s reveal a path toward more targeted treatments?
Tracy Young-Pearse, Ph.D.
Harvard University
Cambridge, MA - United States
Background
Alzheimer's disease is characterized by specific brain changes, however, the biological underpinnings that may lead to these brain changes could be different pathways. This is evident from the differences in disease progression that individuals experience, which may be determined by one's brain blood vessel health, genetic make-up, or levels of disease-related proteins in the brain, blood, and cerebrospinal fluid (CSF, the biological fluid surrounding the brain and spinal cord). This “heterogeneity” of Alzheimer’s has made the search for disease-modifying drugs challenging.
Dr. Tracy Young-Pearse and colleagues believe Alzheimer’s may have different underlying biological causes that contribute to the disease-related brain changes. Specifically, the researchers suggest that many genetic variations associated with risk for and resilience to Alzheimer’s interact to have different impacts on biological pathways, which in turn influence changes in brain biology and cognition.
Research Plan
To study the different biological mechanisms underlying Alzheimer’s, the research team will use a specialized type of stem cell called induced pluripotent stem cells (iPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the body, including brain cells, and grown in laboratory dishes.
Dr. Young-Pearse and colleagues have generated iPSCs from over 100 individuals that span the genomic and clinical spectrum of aging and Alzheimer’s. Based on results from preliminary studies, the team will use these cell lines to further investigate dysregulated biological pathways associated with hyperexcitability in the brain. This is a process that can overstimulate nerve cells and synapses, specialized structures that nerve cells use to send signals to one another, in early Alzheimer’s. However, the underlying mechanisms are not well understood.
The researchers will create nerve cells from iPSCs from a diverse cohort of individuals with Alzheimer’s and with no cognitive impairment. They will study how synapse structure and function, dysregulated protein networks, and hyperexcitability may differ in nerve cells with different genetic backgrounds. Next, the team will study how three genetic variations (SORL1, CLU, and INPP5D) impact synapse structure and function in cells from subsets of individuals with Alzheimer’s. Finally, Dr. Young-Pearse and colleagues will test potential therapies that target different mechanisms that contribute to synaptic dysfunction. They will determine if these therapies impact synapse structure and function and if genetic background influences the degree of responsiveness.
Impact
If successful, this project may shed light on the biological mechanisms underlying Alzheimer’s. Identifying these contributing biology mechanisms will inform the design of future therapies that target different biological pathways impacted by Alzheimer’s as well as inform potential targets for early detection of changes in these biologies.
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