Common variants in the ABCA7 gene are known to increase risk for developing Alzheimer’s disease (AD), particularly in Black people. Interestingly, ABCA7 variants are more strongly linked to AD in Black people than variants in the well-known APOE4 gene. FunGen-AD-funded researchers Badri Vardarajan, Caghan Kizil, and Richard Mayeux were part of an international research team that discovered the role of ABCA7 in AD.
The researchers first knocked out one copy of the abca7 gene in a zebrafish model. This led to reduced proliferation of astrocytes, reduced density of synapses, altered microglial response, and lower expression of neuropeptide Y (NPY) throughout the brain. Injecting a human version of NPY into these abca7 knockout zebrafish rescued astrocyte proliferation and synaptic density. Similar results were seen in experiments with induced pluripotent stem cell-derived human neurons where loss of ABCA7 expression led to reduced NPY expression. Examination of clinical data of AD patients showed that reduced ABCA7 or NPY expression correlates with elevated Braak stages. Further analyses of human data indicated that ABCA7 influences NPY expression. Overall, this study shows that ABCA7 variants accelerate neurodegeneration by reducing the amount of NPY, a protein essential for maintaining astrocyte proliferation and synapse density. Thus, NPY is potential therapeutic target for AD patients who carry these ABCA7 variants.
This research, partially supported by FunGen-AD grants R01AG067501 and RF1AG066107, is published in Cell Genomics here. You can read more about these research findings at the following links:
- Study Shows How Common Genetic Variants in Black Americans Increase Alzheimer’s Risk (Columbia University Irving Medical Center, The Mirage)