The involvement of microglia in Alzheimer's disease: a new dog in the fight

Abstract

First described clinically in 1906, Alzheimer's disease (AD) is the most common neurodegenerative disease and form of dementia worldwide. Despite its prevalence, only five therapies are currently approved for AD, all dealing with the symptoms rather than the underlying causes of the disease. A multitude of experimental evidence has suggested that the once thought inconsequential process of neuroinflammation does, in fact, contribute to the AD pathogenesis. One such CNS cell type critical to this process are microglia. Plastic in nature with varied roles, microglia are emerging as key contributors to AD pathology. This review will focus on the role of microglia in the neuroinflammatory response in AD, highlighting recent studies implicating aberrant changes in microglial function in disease progression. Of critical note is that with these advances, a reconceptualization of the framework in which we view microglia is required. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Figure 1

A proposed new framework for microglia characterization. The M1/M2 paradigm for microglial characterization is now recognized as a vast oversimplification of microglial phenotypes and functions. Rather than pigeonholing these cells as either ‘good’ or ‘bad’, a context‐dependant label, a more appropriate view is to recognize them as a distinct array of overlapping phenotypes. Microglia can in fact have altered expression levels of both classical M1 and M2 markers. This framework also includes shifting away from notions of resting/quiescent and active microglia. Whilst this may seem an issue of semantics, not only does it not dismiss these phenotypes entirely as previously done in the past, it also allows for a more holistic view when interpreting data. For simplicity, morphological differences have not been illustrated. Created with BioRender.

Figure 2

Alterations in microglial phenotype and function as seen in AD. A multitude of experimental evidence has now demonstrated that these changes are indeed deleterious and may in fact contribute to disease progression. Created with BioRender.