2023 Endolysosomal Activity in Alzheimer’s (E2A)
Impact of ABCA7 mutations on the microglial endolysosomal function
Why does beta-amyloid protein accumulate into plaques in Alzheimer’s?
Renzo Mancuso, Ph.D.
Flanders Institute for Biotechnology, VIB
Antwerpen, Belgium
Background
Researchers are focusing on identifying genetic factors that may increase the risk for developing Alzheimer’s. Several studies have identified a gene called ABCA7 that increases risk of Alzheimer’s in some populations. ABCA7 encodes a protein involved in transporting molecules within and across cell membranes, including in microglia cells. Microglia are the primary immune cells in the brain that serve as one of the first defenses against nerve cell damage. Microglia sense and help remove unwanted proteins from the brain, in part through a process called phagocytosis, during which the microglial cells engulf (or “swallow”) the unwanted proteins. Previous work suggests that a lack of ABCA7 interferes with the ability of microglia to do this job, which could contribute to the accumulation of beta-amyloid proteins that form the hallmark plaques of Alzheimer’s.
Research Plan
Dr. Mancuso and team will examine the role of ABCA7 in human microglia cells. They will use a specialized type of stem cell collected from adult human tissue called induced pluripotent stem cells (iPSCs). iPSCs can be re-programmed to grow into any type of cell in the human body, including microglia. To study the effect of ABCA7 on microglia, some of the iPSC microglia will be genetically engineered to lack ABCA7 while others will have normal levels of ABCA7. To understand how these microglia react to beta-amyloid in the brain, these microglia will be injected into the brains of genetically engineered Alzheimer’s like mice which develop beta-amyloid plaques.
After six months, the researchers will collect the injected microglia from the mouse brains and characterize the proteins on the surface of the cells as well as within the cell in order to understand consequences of ABCA7-deficient microglia.
Impact
These experiments will help clarify the role ABCA7 plays in Alzheimer’s, and may suggest novel therapeutic strategies involving microglia.