Deconstructing The Innate Immune Component Of A Molecular Network Of The Aging Frontal Cortex

Alzheimer’s disease is pathologically characterized by the accumulation of neuritic β-amyloid plaques and neurofibrillary tangles in the brain and clinically associated with a loss of cognitive function. The dysfunction of microglia cells has been proposed as one of the many cellular mechanisms that can lead to an increase in Alzheimer’s disease pathology. Investigating the molecular underpinnings of microglia function could help isolate the causes of dysfunction while also providing context for broader gene expression changes already observed in mRNA profiles of the human cortex.
We have used mRNA sequencing to construct gene expression profiles of microglia purified from the cortex of 11 subjects from a longitudinal cohort of aging, Rush Memory Aging Project (MAP). By studying these microglia gene expression profiles in the context of tissue-level profiles of the cortex of 542 subjects from the MAP and Religious Orders Study (ROS) we address dual problems. By using information from the large ROSMAP cohort, we are able to isolate the genes which are strongly associated with immune response. Conversely, we illustrate that the microglia signature can be used to highlight predefined sets of coexpressed genes in ROSMAP that are highly enriched for microglia genes. Addressing these two questions allows us to identify sets of microglia specific genes which are associated with various Alzheimer’s disease traits further emphasizing the molecular consequences of microglia dysfunction in this disease. Specifically, we are able to identify a set of microglia related genes associated with tau and amyloid pathology as well as an activated microglial morphology.