Characterizing Glial Cells in the Human Neuritic Plaque Microenvironment

Background The immune system is complex and serves to maintain our overall health. In our brain, the immune system specifically serves to maintain healthy nerve cells. Microglia are the primary immune cells of the brain and help maintain healthy nerve cells in the brain. Individuals with Alzheimer’s typically experience brain inflammation caused by dysregulation of the immune system, including increased activity of microglia, which can damage the nearby nerve cells. Astrocytes (referred to as “support cells”) are the most numerous cell type in the brain and play an important role in supporting nerve cell function in the brain. Astrocytes help nerve cells communicate through specialized nerve cell structures called “synapses.” Synapses may become damaged in Alzheimer’s and nerve cells are then unable to effectively communicate with one another, which could be associated with a decline in cognition. In preliminary research, Dr. Hans-Ulrich Klein and colleagues used sophisticated molecular biology techniques to analyze brain tissue from genetically engineered Alzheimer’s-like mice and individuals with Alzheimer’s. Their analyses identified specific types of astrocytes and microglia that may be associated with brain changes such as accumulation of beta amyloid in the brain (beta amyloid accumulates to form plaques, one of the hallmark brain changes observed in Alzheimer’s). These astrocytes and microglia may also be associated with cognitive decline in these models. Based on their findings, Dr. Klein believes that that these types of astrocytes and microglia may also be found in brain regions where plaques are present. The researchers believe that this proximity of astrocytes and microglia to plaques, may create “microenvironments” in the brain that could be associated with nerve cell damage and death in Alzheimer’s. Research Plan Building on their preliminary findings, Dr. Klein and his team will study these microenvironments in further detail. For their project, the researchers will use brain tissue from individuals with Alzheimer’s, from the New York Brain Bank (NYBB) at Columbia University. They will study these brain tissue samples, using sophisticated microscopic and genetic analysis techniques to identify how closely the astrocytes and microglia are located to the sites of the plaques in the brain regions. The researchers will then study whether the astrocytes and microglia that are particularly in close proximity to plaques, are also undergoing a process called senescence – an aging process during which the cells become unable to divide. Studies show that the senescent cells tend to accumulate in multiple tissues with aging and may be associated with the release of proteins associated with brain inflammation. Dr. Klein believes that this project could uncover biological mechanisms by which astrocytes and microglia may be associated with brain inflammation observed in Alzheimer’s. Impact The study results could reveal potential insights into how the brain’s immune system may affect Alzheimer’s-specific brain changes. If successful, these results could lead to potential dementia therapies in future that may be aimed at removing these cells close to the plaques and preventing nerve cell damage and death in Alzheimer’s.