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2015 Grants - Cruchaga
Understanding the Role of APP, PSEN1, PSEN2, TREM2 and PLD3 in Alzheimer’s Disease
Carlos Cruchaga, Ph.D.
Washington University in St. Louis
St. Louis, Missouri
2015 Biological Underpinnings of Genetic Risk Factors in Alzheimer’s Disease Grant
How do variations in genes that increase Alzheimer’s risk affect the biological pathways that may be involved in disease onset and progression?
Certain variations in the genes for amyloid-beta precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2) cause a rare form of early-onset familial Alzheimer’s disease. Recent studies have also shown that variations in two other genes, triggering receptor expressed on myeloid cells 2 (TREM2) and phospholipase D3 (PLD3), increase the risk of the more common late-onset Alzheimer’s. These five genes are all thought to affect the production or clearance of beta-amyloid, a protein fragment at the focus of research into the causes of Alzheimer’s disease. Beta-amyloid accumulates into amyloid plaques, a hallmark of Alzheimer’s disease in the brain.
Despite the knowledge that variations in these five genes increase the risk of Alzheimer’s disease, there is limited information about how such variations affect the function of nerve cells or the production or clearance of beta-amyloid. In addition, more research is needed to better understand how changes in these genes may impact other biological pathways involved in Alzheimer’s disease.
Carlos Cruchaga, PhD., and colleagues have proposed a series of studies to help understand how variations in the genes for APP, PSEN1, PSEN2, TREM2 and PLD3 affect the molecular processes that increase risk for Alzheimer’s disease. The researchers will use advanced genetic methods to develop “co-expression networks” to help them identify the main biological pathways that are affected by these genes. They will study how these networks differ in brain tissue from people who (1) had Alzheimer’s and carried the known risk variations of these genes (2) had Alzheimer’s but did not have the risk variations of these genes, and (3) people who were cognitively healthy (e.g. the control group). This will allow the researchers to determine which biological pathways are abnormal in people at risk for Alzheimer’s. Knowing this information is important for designing specific therapies based on a person’s genetics.
These studies will provide new information about how variations in specific genes lead to cellular changes that increase the risk for Alzheimer’s. The results could help scientists better understand the causes of Alzheimer’s disease and inform new techniques for determining who is at high risk for the disease. Importantly, these findings could lead to the identification of specific targets for novel treatments.