Microglial priming in neurodegenerative disease
Abstract
Under physiological conditions, the number and function of microglia--the resident macrophages of the CNS--is tightly controlled by the local microenvironment. In response to neurodegeneration and the accumulation of abnormally folded proteins, however, microglia multiply and adopt an activated state--a process referred to as priming. Studies using preclinical animal models have shown that priming of microglia is driven by changes in their microenvironment and the release of molecules that drive their proliferation. Priming makes the microglia susceptible to a secondary inflammatory stimulus, which can then trigger an exaggerated inflammatory response. The secondary stimulus can arise within the CNS, but in elderly individuals, the secondary stimulus most commonly arises from a systemic disease with an inflammatory component. The concept of microglial priming, and the subsequent exaggerated response of these cells to secondary systemic inflammation, opens the way to treat neurodegenerative diseases by targeting systemic disease or interrupting the signalling pathways that mediate the CNS response to systemic inflammation. Both lifestyle changes and pharmacological therapies could, therefore, provide efficient means to slow down or halt neurodegeneration.
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Excessive inflammatory response occurs in many neurodegenerative disorders such as Parkinson's (PD) and Alzheimer's diseases (AD).
“This excessive inflammatory response occurs in many neurodegenerative disorders such as Parkinson's (PD) and Alzheimer's diseases (AD) (Ransohoff, 2016),(Perry and Holmes, 2014),(Burguillos et al., 2011),(Abeliovich and Gitler, 2016), as well as in neurological conditions such as ischemic stroke (Lambertsen et al., 2012),(Burguillos et al., 2015).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Perry and Holmes, 2014
The cause of microglial priming is unclear and likely results from multiple factors, including loss of inhibitory ligand-receptor communication with aging neurons, interactions with age-related misfolded proteins such as Aβ, age-related exposure to increasing transforming growth factor-β, age-related alterations in production of IL-4 and CCL11 in the choroid plexus, and unique microenvironmental 3
“The cause of microglial priming is unclear and likely results from multiple factors, including but not limited to (1) a loss of inhibitory ligand–receptor communication with aging neurons (94), (2) interactions with age-related misfolded proteins such as Aβ which promote pro-inflammatory cytokine production (95), (3) age-related exposure to increasing transforming growth factor-β which could”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [94]
The primed state is thought to make aged microglia disproportionately reactive to immunological challenges, leading to prolonged neuroinflammation and cognitive deficits associated with age.
“This state of ‘priming’ is thought to make aged microglia disproportionately reactive to immunological challenges, leading to prolonged neuroinflammation and the cognitive deficits associated with age [65,66].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [66]
With aging, microglia take on a 'primed' phenotype, which is characterized by an exaggerated and uncontrolled inflammatory response to an immune stimulus.
“With aging, microglia take on a 'primed' phenotype, which is characterized by an exaggerated and uncontrolled inflammatory response to an immune stimulus (Perry and Holmes, 2014).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Perry and Holmes, 2014
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Microbiome–microglia connections via the gut–brain axis
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Microglia Priming with Aging and Stress
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TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease
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“A persistent homeodynamic imbalance, such as brain accumulation of Aβ, can trigger a step further in activation, referred to as “priming” (37).”
BackgroundMicroglial Physiology and Pathophysiology: Insights from Genome-wide Transcriptional Profiling
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Mechanisms of Molecular Mimicry Involving the Microbiota in Neurodegeneration
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Microglial Dynamics and Role in the Healthy and Diseased Brain: A Paradigm of Functional Plasticity
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Self-citationInnate Immunity and Neurodegeneration
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The role of neuroimmune signaling in alcoholism
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16S rRNA Next Generation Sequencing Analysis Shows Bacteria in Alzheimer’s Post-Mortem Brain
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Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity
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Microglial phenotypes in Parkinson’s disease and animal models of the disease
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Microbiota regulation of the mammalian gut-brain axis
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Hidden wounds? inflammatory links between childhood trauma and psychopathology
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TREM2-Ligand Interactions in Health and Disease
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“Whether by contact with plaques or other insults, microglia become primed for excessive inflammatory responses [62].”
BackgroundMicroglia and the aging brain: are senescent microglia the key to neurodegeneration?
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Cross talk: the microbiota and neurodevelopmental disorders
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Microglial repopulation resolves inflammation and promotes brain recovery after injury: RICE et al.
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“Microglia become primed with age, disease, and injury, wherein they fail to resolve insults and instead remain chronically activated (Holtman et al., 2015; Perry & Holmes, 2014; Wes, Holtman, Boddeke, Moller, & Eggen, 2016).”
BackgroundPeripheral immune system in aging and Alzheimer’s disease
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- Authors
- Perry, V. H., & Holmes, C.
- Affiliations
- University of Southampton (GB)
- Corresponding author
- Perry, V. Hugh
- Venue
- Nature Reviews Neurology
- Published
- 2014-03-18
- Volume
- 10
- Issue
- 4
- Pages
- 217-224
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- OpenAlex
- W2059996790
- Cited by
- 1,127
- References
- 121
- Citations by year
- 2026: 106 · 2025: 93 · 2024: 86 · 2023: 69 · 2022: 88 · 2021: 97 · 2020: 104 · 2019: 90 · 2018: 119 · 2017: 106 · 2016: 86 · 2015: 65 · 2014: 18
- FWCI
- 7.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- Wellcome Trust
- National Academy of Sciences of Ukraine
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- microglial priming, neurodegeneration, microglial activation, secondary inflammation, systemic inflammation, diabetes mellitus, microglial proliferation, neuroinflammation, neurodegenerative disease treatment, lifestyle intervention
- MeSH terms
- Alzheimer Disease, Animals, Anti-Inflammatory Agents, Brain, Central Nervous System Diseases, Humans, Inflammation, Macrophage Activation, Microglia, Neurodegenerative Diseases
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