Microglial Activation and Neuroinflammation in Neurodegenerative Disorders

Microglia are the resident immune cells of the central nervous system, responsible for surveillance, clearance of debris and modulation of neuronal support. In neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis, microglial activation underpins a spectrum of neuroinflammatory processes that can be both protective and injurious. Acute activation may facilitate clearance of protein aggregates and promote tissue repair, whereas chronic activation sustains a pro-inflammatory milieu through persistent release of cytokines, chemokines and reactive oxygen species. Age-related changes in microglial function, including glial senescence and dysregulated phagocytosis, further compromise neuronal resilience and amplify pathological protein spread. The dynamic balance between neuroprotective and neurotoxic microglial states is influenced by transcriptional programmes, epigenetic modulation and systemic factors. Understanding these complex interactions is central to developing therapies that recalibrate microglial responses, attenuate harmful inflammation and preserve cognitive and motor function in ageing populations worldwide.

Research from Nature Portfolio

Recent studies have proposed that ageing drives accumulation of amyloid-β and tau aggregates, which in turn induce a senescent microglial phenotype. This glial senescence sustains an inflammatory feedback loop, promoting further pathology accumulation and transition from healthy cognition to mild cognitive impairment. Such work highlights the central role of local microglial ageing in disease onset and progression.

High-resolution transcriptional and epigenetic mapping of microglia from juvenile to aged mice has revealed sex-specific gene signatures and age-dependent microglial programmes. An innovative microglial turnover model demonstrated that aged-like microglia in a young brain are sufficient to impair cognition, emphasising that intrinsic alterations in microglia drive neurodegenerative processes independently of other aged cell types.

Microglial Activation and Neuroinflammation in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in microglial activation and neuroinflammation in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Microglia: Resident immune cells of the central nervous system that maintain homeostasis and mediate inflammatory responses.

Neuroinflammation: Inflammatory processes within the central nervous system, often driven by microglial activation and characterised by cytokine release.

Glial senescence: Age-related decline in glial cell function leading to a sustained pro-inflammatory state and reduced neuroprotection.

Polarisation (M1/M2): Functional states of microglia characterised by pro-inflammatory (M1) or anti-inflammatory/neuroprotective (M2) profiles.

Epigenetic modulation: Heritable changes in gene expression that do not involve alterations to the underlying DNA sequence, influencing microglial identity and function.

References

1. An aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease. Nature Communications (2023).
2. Transcriptional and epigenetic decoding of the microglial aging process. Nature Aging (2023).
3. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Translational Neurodegeneration (2020).
4. Microglia Polarization From M1 to M2 in Neurodegenerative Diseases. Frontiers in Aging Neuroscience (2022).