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Published on: December 26, 2016
Microglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States
Madison K Kuhn1,2,3,4, Elizabeth A Proctor1,2,3,4,5,6
1Department of Biomedical Engineering, The Pennsylvania State University, University Park, Pennsylvania, USA.
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.
Insights
Microglia dysfunction in Alzheimer's disease (AD) contributes to pathology. Studying human microglia models alongside mouse models is crucial for understanding their complex roles and developing effective immunotherapies.
Area of Science:
- Neuroimmunology
- Alzheimer's Disease Pathogenesis
Background:
- Microglia, the brain's immune cells, are dysfunctional in Alzheimer's disease (AD).
- Their aberrant immune responses contribute to pathological protein accumulation and neuronal damage.
- Genetic links and the potential for immunomodulatory therapies highlight microglia as a key research focus in AD.
Purpose of the Study:
- To review microglial immune signaling and responses in Alzheimer's disease.
- To explore the role of induced pluripotent stem cell (iPSC)-derived human microglia models.
- To discuss the complementary insights and limitations of mouse and iPSC-derived models for understanding microglial dysfunction in AD.
Main Methods:
- Review of existing literature on microglial immune signaling in AD.
- Analysis of findings from transgenic mouse models of AD.
- Exploration of studies utilizing human iPSC-derived microglia.
Main Results:
- Microglia exhibit diverse, context-dependent functional states in AD, with both protective and detrimental roles.
- Mouse models provide evidence for microglial involvement in AD pathology, but results can be contradictory.
- Human iPSC-derived microglia offer a valuable model for studying human-specific microglial responses in AD.
Conclusions:
- Understanding microglial dysfunction in AD requires integrating data from various models.
- Both mouse and iPSC-derived models have limitations, necessitating a comprehensive approach.
- An integrated view across complementary models is essential for advancing therapeutic strategies for Alzheimer's disease.
