Defining Microglial Phenotypes in Alzheimer’s Disease

Abstract

The concept of activated microglia being associated with neurodegenerative pathological structures in aging and Alzheimer’s disease (AD) has been well established, but questions remain about how well are we defining “what are microglia actually doing” when we look at diseased or aged brains? Most studies of microglia in human AD brains have employed a limited set of antigenic markers, particularly the major histocompatibility complex protein HLA-DR and ionized calcium-binding adaptor molecule IBA-1, along with cellular morphological criteria, but in recent years, it has been appreciated that microglial responses are very heterogeneous depending on their surrounding environment—every microglia might be different. Initial observations on human brain microglia associated with plaques and tangles suggested that microglial inhibition with broad spectrum anti-inflammatory drugs should slow down AD pathology, but clinical trials did not show this approach to be effective. In this article, we will consider the needs, challenges and benefits for refining how microglia are defined as they associate with pathological proteins. This may aid in defining which ones are accelerating neurotoxicity and which ones are performing reparative/phagocytic functions. More complete definition of microglial phenotypes offers the potential of developing targeted anti-inflammatory approaches for this disease.