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Microglial Priming and Alzheimer's Disease: A Possible Role for (Early) Immune Challenges and Epigenetics?
Lianne Hoeijmakers1, Yvonne Heinen1, Anne-Marie van Dam2
1Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam Amsterdam, Netherlands.
Abstract:
Neuroinflammation is thought to contribute to Alzheimer's disease (AD) pathogenesis that is, to a large extent, mediated by microglia. Given the tight interaction between the immune system and the brain, peripheral immune challenges can profoundly affect brain function. Indeed, both preclinical and clinical studies have indicated that an aberrant inflammatory response can elicit behavioral impairments and cognitive deficits, especially when the brain is in a vulnerable state, e.g., during early development, as a result of aging, or under disease conditions like AD. However, how exactly peripheral immune challenges affect brain function and whether this is mediated by aberrant microglial functioning remains largely elusive. In this review, we hypothesize that: (1) systemic immune challenges occurring during vulnerable periods of life can increase the propensity to induce later cognitive dysfunction and accelerate AD pathology; and (2) that "priming" of microglial cells is instrumental in mediating this vulnerability. We highlight how microglia can be primed by both neonatal infections as well as by aging, two periods of life during which microglial activity is known to be specifically upregulated. Lasting changes in (the ratios of) specific microglial phenotypes can result in an exaggerated pro-inflammatory cytokine response to subsequent inflammatory challenges. While the resulting changes in brain function are initially transient, a continued and/or excess release of such pro-inflammatory cytokines can activate various downstream cellular cascades known to be relevant for AD. Finally, we discuss microglial priming and the aberrant microglial response as potential target for treatment strategies for AD.
Insights
Peripheral immune challenges can prime microglia, increasing Alzheimer's disease (AD) risk. This microglial priming, especially during vulnerable life stages, may accelerate AD pathology and cognitive decline.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Neuroinflammation, driven by microglia, is implicated in Alzheimer's disease (AD) pathogenesis.
- Peripheral immune system activation can significantly impact brain function, particularly in vulnerable states like aging or disease.
- The precise mechanisms by which peripheral immune challenges affect brain function and microglial activity in AD remain unclear.
Purpose of the Study:
- To hypothesize that systemic immune challenges during vulnerable life periods can heighten susceptibility to cognitive dysfunction and AD pathology.
- To propose that microglial priming is a key mechanism mediating this vulnerability.
- To explore the role of microglial priming in AD pathogenesis and its potential as a therapeutic target.
Main Methods:
- Review of preclinical and clinical studies on neuroinflammation, microglial function, and AD.
- Analysis of the impact of systemic immune challenges on brain function and cognitive deficits.
- Discussion of microglial priming by neonatal infections and aging.
Main Results:
- Systemic immune challenges during vulnerable periods may predispose individuals to later cognitive dysfunction and accelerated AD pathology.
- Microglial priming, induced by factors like neonatal infection or aging, leads to altered microglial phenotypes.
- Primed microglia exhibit an exaggerated pro-inflammatory cytokine response, potentially activating AD-relevant cellular cascades.
Conclusions:
- Microglial priming is a critical factor in linking peripheral immune challenges to AD pathogenesis.
- Aberrant microglial responses following priming may contribute to cognitive deficits and AD progression.
- Targeting microglial priming and aberrant microglial activation presents a promising therapeutic strategy for AD.
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