Microglial Senescence and Activation in Healthy Aging and Alzheimer's Disease: Systematic Review and
Antonio Malvaso1, Alberto Gatti1, Giulia Negro2
1IRCCS "C. Mondino" Foundation, National Neurological Institute, Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy.
Abstract:
The greatest risk factor for neurodegeneration is the aging of the multiple cell types of human CNS, among which microglia are important because they are the "sentinels" of internal and external perturbations and have long lifespans. We aim to emphasize microglial signatures in physiologic brain aging and Alzheimer's disease (AD). A systematic literature search of all published articles about microglial senescence in human healthy aging and AD was performed, searching for PubMed and Scopus online databases. Among 1947 articles screened, a total of 289 articles were assessed for full-text eligibility. Microglial transcriptomic, phenotypic, and neuropathological profiles were analyzed comprising healthy aging and AD. Our review highlights that studies on animal models only partially clarify what happens in humans. Human and mice microglia are hugely heterogeneous. Like a two-sided coin, microglia can be protective or harmful, depending on the context. Brain health depends upon a balance between the actions and reactions of microglia maintaining brain homeostasis in cooperation with other cell types (especially astrocytes and oligodendrocytes). During aging, accumulating oxidative stress and mitochondrial dysfunction weaken microglia leading to dystrophic/senescent, otherwise over-reactive, phenotype-enhancing neurodegenerative phenomena. Microglia are crucial for managing Aβ, pTAU, and damaged synapses, being pivotal in AD pathogenesis.
Insights
Microglia, the brain's sentinels, change with aging and Alzheimer's disease (AD). Understanding these microglial shifts is key to brain health and developing new AD therapies.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Aging is the primary risk factor for neurodegeneration.
- Microglia, the central nervous system's immune cells, are crucial sentinels with long lifespans.
- Understanding microglial roles in brain aging and Alzheimer's disease (AD) is vital.
Approach:
- A systematic literature search was conducted using PubMed and Scopus.
- 1947 articles were screened, with 289 assessed for full-text eligibility.
- Microglial transcriptomic, phenotypic, and neuropathological profiles in healthy aging and AD were analyzed.
Key Points:
- Human and mouse microglia exhibit significant heterogeneity.
- Microglial function can be context-dependent, acting protectively or harmfully.
- Aging-related oxidative stress and mitochondrial dysfunction impair microglia, promoting neurodegeneration.
Conclusions:
- Microglia are pivotal in managing amyloid-beta, tau pathology, and synaptic damage in AD.
- Maintaining microglial homeostasis is essential for brain health.
- Further research is needed to fully elucidate human microglial behavior in aging and AD.
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