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The Role of Microglia in Sporadic Alzheimer's Disease
Wolfgang J Streit1, Habibeh Khoshbouei1, Ingo Bechmann2
1Department of Neuroscience, University of Florida, Gainesville, FL, USA.
Abstract:
Microglia constitute the brain's immune system and their involvement in Alzheimer's disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer's disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea.
Insights
Microglia dysfunction, not overactivation, may drive Alzheimer's disease. Aging causes microglial senescence, impairing their neuroprotective functions and leading to neuronal degeneration.
Area of Science:
- Neuroscience
- Immunology
- Gerontology
Background:
- Microglia are the brain's immune cells.
- Current Alzheimer's disease (AD) theories often portray microglia as harmful, overactivated by amyloid plaques and causing neuroinflammation.
- This amyloid/neuroinflammation cascade hypothesis is challenged by the significant role of aging in AD pathogenesis.
Purpose of the Study:
- To present and discuss the microglial dysfunction theory as an alternative to the amyloid cascade hypothesis for Alzheimer's disease.
- To highlight the role of aging and microglial senescence in AD.
- To review human evidence supporting microglial dysfunction in AD.
Main Methods:
- Review of existing human evidence.
- Comparative analysis of the amyloid/neuroinflammation cascade hypothesis and the microglial dysfunction theory.
- Focus on the etiological role of aging in sporadic Alzheimer's disease.
Main Results:
- The amyloid/neuroinflammation hypothesis primarily relies on genetic data.
- The microglial dysfunction theory incorporates aging as a key factor, aligning with aging being the primary risk factor for sporadic AD.
- Human evidence is presented that supports the concept of senescent microglial dysfunction.
Conclusions:
- Aging-induced microglial senescence leads to dysfunction, impairing neuroprotective roles.
- Impaired microglia fail to support aging neurons, contributing to neurodegeneration in Alzheimer's disease.
- The microglial dysfunction theory offers a compelling alternative explanation for sporadic Alzheimer's disease, emphasizing aging over amyloid-induced inflammation.
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