Microglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States

Abstract

Microglia, the resident immune-competent cells of the brain, become dysfunctional in Alzheimer's disease (AD), and their aberrant immune responses contribute to the accumulation of pathological proteins and neuronal injury. Genetic studies implicate microglia in the development of AD, prompting interest in developing immunomodulatory therapies to prevent or ameliorate disease. However, microglia take on diverse functional states in disease, playing both protective and detrimental roles in AD, which largely overlap and may shift over the disease course, complicating the identification of effective therapeutic targets. Extensive evidence gathered using transgenic mouse models supports an active role of microglia in pathology progression, though results vary and can be contradictory between different types of models and the degree of pathology at the time of study. Here, we review microglial immune signaling and responses that contribute to the accumulation and spread of pathological proteins or directly affect neuronal health. We additionally explore the use of induced pluripotent stem cell (iPSC)-derived models to study living human microglia and how they have contributed to our knowledge of AD and may begin to fill in the gaps left by mouse models. Ultimately, mouse and iPSC-derived models have their own limitations, and a comprehensive understanding of microglial dysfunction in AD will only be established by an integrated view across models and an appreciation for their complementary viewpoints and limitations.

Keywords: Alzheimer's disease; amyloid‐β; microglia; protein aggregation; proteinopathy; tau protein.

FIGURE 1

The combined actions of an evolving population of diverse microglial activation states contribute to Alzheimer's disease progression. Following an immune stimulus, microglia become activated in an effort to restore brain homeostasis. Commonly observed activation states in aging and neurodegenerative disease include primed, disease‐associated, phagocytic, and senescent microglia. Transcriptomic studies have identified a vast diversity of activation states of unknown function, and a comprehensive classification of microglial states has not been defined. Each individual state can independently contribute beneficially and/or detrimentally to AD pathology, such as the clearance or spread of misfolded proteins by phagocytic microglia or the amplified secretion of pro‐inflammatory cytokines by primed and disease‐associated microglia contributing to neuronal injury and the hyperphosphorylation of tau. The composite population of microglia, however, and its combinatorial effect of individual states drive disease. The distribution of microglial activation states and subsequent dominant downstream activities and effect on AD pathology evolves over the course of disease. Functional characterization of microglial states and their relative frequency in progressing AD is needed for the identification of successful therapeutic targets to restore beneficial microglial function or reduce detrimental dysfunction within optimal treatment windows. Created with BioRender.com.