2023 Endolysosomal Activity in Alzheimer’s (E2A)
Understanding the role of AD endocytic risk genes in disease pathogenesis.
How does the brain’s waste disposal system contribute to Alzheimer’s?
Natalie Connor-Robson, Ph.D.
Cardiff University
Cardiff, United Kingdom
Background
Alzheimer’s is associated with hallmark brain changes including the accumulation of the proteins beta-amyloid and tau into abnormal plaques and tangles, respectively. Alzheimer’s is a complex disease and there are still many questions surrounding these brain changes. One question is why the accumulation of beta-amyloid to form plaques begins, despite the brain having a robust waste disposal system.
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. Research has shown that microglia become impaired in Alzheimer’s and may lose their ability to clear unwanted molecules and proteins properly.
Research Plan
Dr. Natalie Connor-Robson suggests that specific genetic variations may influence how well microglia function at clearing waste. The researchers will study a specialized type of stem cell collected from adult human tissue called human induced pluripotent stem cells (hiPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the human body and grown in laboratory dishes, including microglia. The team will collect cells from individuals who carry multiple genetic variations related to the waste removal system. The microglia will be stained with fluorescent markers that, through microscopic imaging, will highlight compartments inside the microglia called lysosomes that are involved in protein uptake, sorting, recycling, and degradation. Live imaging will also be used to assess how well these microglia uptake beta-amyloid proteins, and how well they breakdown waste.
Impact
These experiments will help to identify any links between Alzheimer’s and microglia function, and potentially point to therapeutic strategies that may increase waste clearance.