As one of the primary resident cell types of the central nervous system (CNS), microglia play a vital role in neurodevelopment, injury repair, and maintenance of homeostasis in the brain and spinal cord. When these foundational functions are impaired, however, microglia can actively contribute to pathogenic processes and drive neurodegeneration.
Research increasingly implicates altered microglial function in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and frontotemporal dementia (FTD).[1] Yet understanding exactly how microglia contribute to these conditions is complicated by the remarkable plasticity of these cells. Rather than simply switching between “resting” and “activated” forms, microglia can adopt diverse functional states shaped by their location, local microenvironment, age, genetics, and disease stage. Recent research has increasingly characterized microglia as a heterogeneous population whose functional states can shift substantially in response to changes in the CNS environment. Because these dynamic states can reflect key disease-related alterations in the CNS, microglia are a promising area of focus for biomarker development.
As researchers investigate microglia as potential sources of biomarkers and therapeutic targets, accurately distinguishing these states and their relation to disease states is becoming increasingly important. Advances in single-cell and single-nucleus sequencing, spatial techniques, and protein-level detection are providing a more detailed picture of microglial heterogeneity, while also revealing how much remains to be understood.
Microglia are the resident macrophages of the CNS and an important component of its innate immune system. Making up approximately 10% of cells throughout the brain and spinal cord, they continuously survey their local environment and respond to signals from neurons and other CNS cells.[2] Their surveillance supports functions extending well beyond immune defense. Microglia participate in the development and refinement of neural circuits and clear dying cells, cellular debris, and abnormal protein aggregates through phagocytosis.[3]
Microglia also maintain continuous bidirectional communication with neurons and other glial cells through a diverse range of direct and indirect mechanisms. Neuronal signals help microglia closely monitor changes in neuronal activity and tissue health, modulating inflammation and immune activity. Simultaneously, microglia release cytokines, chemokines, growth factors, and other mediators that can influence neuronal function and the behavior of astrocytes and oligodendrocytes.[4] This coordinated crosstalk allows microglia to rapidly adapt their activity in response to changes in the CNS environment, supporting homeostasis under healthy conditions and shaping inflammatory responses during injury or disease.
Microglia in Neuroinflammation and Neurodegenerative Disease
Following injury or cellular stress, changes in signaling can recruit microglia to affected areas and trigger shifts in morphology, metabolism, gene expression, and function. These responses can promote clearance of harmful material and support tissue repair, but the same mechanisms can become detrimental when microglial responses are prolonged or dysregulated.[5] This balance between protective and potentially cytotoxic activity is one reason microglia have become such an important focus in neurodegenerative disease research.
In diseases such as AD, for example, microglia can interact directly with amyloid-β deposits and participate in their clearance and containment. At the same time, persistent exposure to misfolded proteins, damaged cells, and inflammatory signals can contribute to sustained changes in microglial function.[6] Microglia produce cytokines, chemokines, complement components, and other inflammatory mediators, potentially contributing to a chronic neuroinflammatory environment.
TREM2 (triggering receptor expressed on myeloid cells 2) plays a key role in maintaining the neuroinflammatory equilibrium, making it a pertinent biomarker candidate in AD. As phosphorylated tau and amyloid-β can trigger microglial activation and secretion of proinflammatory mediators, TREM2 attenuates the inflammatory cascade. TREM2 dysfunction exacerbates neuroinflammatory processes, with numerous TREM2 variants linked to increased risk of AD and other neurodegenerative diseases.[7] Similarly, apolipoprotein E (APOE) is another microglial protein of interest in neurodegenerative disease research, with various APOE alleles associated with diverse microglial phenotypes. These alleles differentially regulate microglial activation, inflammatory responses, and other key functions, in turn contributing to AD pathology.[8]
Historically, researchers often described microglial activation using an M1/M2 categorization derived from macrophage biology—M1 microglia were broadly characterized as pro-inflammatory and potentially neurotoxic, while M2 microglia were associated with anti-inflammatory activity, tissue repair, and neuroprotection.[9][10] While this framework offered a useful starting point for understanding different microglial functions, it is now considered an oversimplification. Rather than falling neatly into two categories, microglia instead appear to occupy a dynamic continuum of molecular and functional states shaped by many factors including brain region, age, disease environment, and signals from neighboring cells.[11] The dualistic M1/M2 approach fails to capture the depth and breadth of changes in microglia over time and within different states of health and disease, thus limiting researchers’ ability to truly understand their function and relevance in various pathologies.
Advances in single-cell RNA sequencing (scRNA-seq), single-nucleus RNA sequencing (snRNA-seq), and related technologies have helped reveal this complexity by identifying transcriptionally distinct microglial populations that may be obscured in bulk measurements.[12] One prominent example is disease-associated microglia (DAM), a state identified in postmortem human tissue as well as models of neurodegeneration and characterized by changes in pathways related to phagocytosis, lipid metabolism, and immune activity. DAM-associated transitions can include decreased expression of genes associated with homeostatic microglia, including P2RY12, CX3CR1, and TMEM119, alongside increased expression of genes such as APOE, TREM2, LPL, and others associated with disease-related processes.[13]
Even DAM, however, should not be viewed as a single universal disease phenotype. Researchers have described numerous microglial states associated with aging, inflammation, white matter injury, lipid metabolism, and neurodegenerative pathology, and the terminology used to describe these populations continues to evolve. The same microglial population may also exhibit different properties depending on disease stage or its location relative to pathological features.[14] As a result, the field is increasingly moving away from asking whether microglia are simply “activated” and toward understanding which functional states are present, what prompted those states, and what the cells are doing within a particular biological context.
This heterogeneity has important implications for how microglia are studied. Commonly used markers can provide valuable information about cellular identity and function, but no individual marker can fully define a microglial state. Proteins such as AIF1/Iba1 are frequently used to identify microglia and other myeloid cells, while TMEM119 and P2RY12 are commonly associated with homeostatic microglia. Other targets, including TREM2, CD33, CX3CR1, CSF1R, cytokines, and components of the complement system, can provide information about intricacies of microglial biology.[15]
The challenge is that expression of these markers is dynamic and can change as microglia respond to their environment. P2RY12, CX3CR1, and TMEM119, for example, are often downregulated during transitions from homeostasis toward certain disease-associated states.[16] Meanwhile, increased expression of a disease-associated marker does not necessarily establish whether a microglial population is protective, harmful, or performing different functions simultaneously. Studies of microglial heterogeneity have highlighted distinct populations that may share expression of individual biomarkers while differing in broader molecular signatures and potentially in their roles during neurodegeneration, underscoring the limitations of using any single marker to define microglial function.[17]
Newer research approaches are helping address these limitations. scRNA-seq and snRNA-seq can identify transcriptionally distinct populations, while spatial transcriptomics and imaging approaches can add critical information about where those cells occur in relation to neurons, protein aggregates, or other pathological features.[18] Proteomic measurements can then help researchers determine whether transcriptional differences translate into changes in protein abundance and localization.[19] Combining these approaches with functional assays provides an opportunity to connect molecular signatures with microglial activity.
The complexity of microglial biology also presents both opportunities and challenges for biomarker development. Rather than measuring neuronal damage alone, microglia-associated biomarkers could potentially provide information about the immune and inflammatory processes occurring alongside neurodegeneration. A growing range of candidate markers is being investigated in cerebrospinal fluid (CSF), blood, tissue, and imaging studies, including soluble TREM2 (sTREM2), CSF1R-associated markers, cytokines, complement proteins, and other molecules linked to microglial function.[20]
sTREM2 provides a useful example of both the potential and difficulty of this approach. TREM2 is a microglial receptor involved in cellular responses to tissue damage, and its soluble form can be detected in CSF and plasma. Studies of sTREM2 have linked changes in CSF levels with neurological disease and microglial responses, making it an intriguing candidate for understanding aspects of neuroinflammation. However, sTREM2 levels can be influenced by genetics, physiological conditions, and disease stage, and its precise biological functions remain under investigation.[21] More broadly, a measurable change in a microglia-associated protein may reflect altered cell abundance, a transition between functional states, or only one component of a larger inflammatory response.
These limitations do not diminish the potential value of microglial biomarkers, but they do reinforce the importance of biological context. A recent review of microglia-related biomarkers in neurodegenerative disease highlights numerous candidates under investigation while noting that many still require additional validation before they can be translated into clinical applications.[22] Understanding which microglial processes are actually represented by a biomarker will be critical if these measurements are to help researchers characterize disease progression, stratify patients, or evaluate responses to therapies.
As the field’s understanding of microglia becomes more nuanced, the tools used to study them must evolve as well. Distinguishing homeostatic, disease-associated, and other microglial states requires more than simply detecting whether microglia are present. Researchers increasingly need to evaluate combinations of markers and connect those molecular signatures with cell location, morphology, and function.
Sensitive, specific, and well-validated antibodies targeting proteins such as TREM2, TMEM119, P2RY12, CX3CR1, Iba1, CD33, CSF1R, and complement-associated proteins can help researchers investigate microglial identity and function across experimental models and disease states. Used alongside transcriptomic, spatial, and functional approaches, these tools can provide a more complete picture of how microglia respond to their changing environment.
As researchers continue to uncover new microglial populations and functional states, it is becoming overwhelmingly clear that “microglial activation” is not a single biological phenomenon. Capturing this complexity will be essential to understanding when microglia protect the nervous system, when their altered functions contribute to neurodegeneration, and how these dynamic cells might ultimately provide new opportunities for disease biomarkers and therapeutic intervention.
Aviva Systems Biology offers a comprehensive catalog of powerful, validated antibody tools to advance your microglial research with unmatched sensitivity and precision, including antibodies targeting TREM2, Iba1 (AIF1), CD68, and beyond.
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[2] Colonna, Marco, and Oleg Butovsky. “Microglia Function in the Central Nervous System During Health and Neurodegeneration.” Annual review of immunology vol. 35 (2017): 441-468. doi:10.1146/annurev-immunol-051116-052358
[3] Borst, Katharina et al. “Microglia: Immune and non-immune functions.” Immunity vol. 54,10 (2021): 2194-2208. doi:10.1016/j.immuni.2021.09.014
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[8] Liu A, Wang T, Yang L, Zhou Y. The APOE-Microglia Axis in Alzheimer's Disease: Functional Divergence and Therapeutic Perspectives-A Narrative Review. Brain Sci. 2025;15(7):675. Published 2025 Jun 23. doi:10.3390/brainsci15070675
[9] Sica, Antonio, and Alberto Mantovani. “Macrophage plasticity and polarization: in vivo veritas.” The Journal of clinical investigation vol. 122,3 (2012): 787-95. doi:10.1172/JCI59643
[10] Guo, Shenrui et al. “Microglia Polarization From M1 to M2 in Neurodegenerative Diseases.” Frontiers in aging neuroscience vol. 14 815347. 16 Feb. 2022, doi:10.3389/fnagi.2022.815347
[11] Dadwal, Shilauni, and Michael T Heneka. “Microglia heterogeneity in health and disease.” FEBS open bio vol. 14,2 (2024): 217-229. doi:10.1002/2211-5463.13735
[12] Gerrits, Emma, et al. "Transcriptional profiling of microglia; current state of the art and future perspectives." Glia 68.4 (2020): 740-755.
[13] Cheng, Yi-Hsuan, and Margaret S Ho. “Disease-associated microglia in neurodegenerative diseases: Friend or foe?.” PLoS biology vol. 23,10 e3003426. 21 Oct. 2025, doi:10.1371/journal.pbio.3003426
[14] Ishikawa, Kentaro et al. “Microglia in Brain Aging and Age-Related Diseases: Friends or Foes?.” International journal of molecular sciences vol. 26,23 11494. 27 Nov. 2025, doi:10.3390/ijms262311494
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[16] Lier, Julia et al. “Beyond Activation: Characterizing Microglial Functional Phenotypes.” Cells vol. 10,9 2236. 28 Aug. 2021, doi:10.3390/cells10092236
[17] Li, Chaoyi et al. “The heterogeneity of microglial activation and its epigenetic and non-coding RNA regulations in the immunopathogenesis of neurodegenerative diseases.” Cellular and molecular life sciences : CMLS vol. 79,10 511. 6 Sep. 2022, doi:10.1007/s00018-022-04536-3
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[22] Volonté, Cinzia, et al. "Neuroprotection beyond neurons: Integrated biomarker-based and astroglia-or microglia-targeted approaches to combat neurodegenerative diseases." Exploration of Neuroprotective Therapy 6 (2026): 1004136.