Skip to content
Frontiers
Search

Perspective

Frontiers in Neuroscience ·

Volume 20 - 2026 | https://doi.org/10.3389/fnins.2026.1916561

Neuroimmune phenotypes in brain aneurysms and neurodegenerative diseases

  • Francis J. Lauzier1
  • David C. Lauzier2*corresponding author
  1. 1Department of Neurology, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI, United States
  2. 2Division of Neuropathology, University of California, Los Angeles, Los Angeles, CA, United States
Article metrics0 viewsView details
PDFCiteMetrics

Abstract

Aneurysmal subarachnoid hemorrhage is a devastating neurological disease that occurs downstream of abnormal dilation of cerebral vessels and weakening of the vessel wall due to underlying inflammation. Vascular endothelial inflammation has been identified as a critical driver of aneurysm growth and progression, with numerous immune cell populations proposed to have a role in this process. The innate immune cells that partake in the process of aneurysm growth, primarily macrophages, can adopt pro-inflammatory or anti-inflammatory phenotypes. A recent line of work implicates an imbalance in macrophage phenotypes as a critical feature in the progression of cerebral aneurysmal disease. An imbalance in immune cell states is also observed in neurodegenerative processes, where the inflammatory phenotypes of microglia and astrocytes appear to be involved in disease progression. Understanding cerebral aneurysms and neurodegeneration as processes that involve inflammatory imbalances may provide a window for future research and identification of therapeutic targets, where modulating immune phenotypes has the potential to reduce both aneurysm rupture risk and neurodegenerative progression. Further, advances in treatments for one disease could be cautiously applied in preclinical models for the other.

Keywords

Introduction

Neurovascular inflammation is an important driver in numerous neurological diseases that elicit a high population burden, both in the United States and globally (Salvarani et al., 2007; Tian et al., 2022). Since immunotherapy has been used with success in several classes of neurological diseases, targeted investigation into neurovascular inflammation may unveil new avenues of experimental targeting that can be eventually translated into the clinical setting (Golde and Levey, 2023; Bourque and Hawiger, 2021). This may be applicable to structural cerebrovascular diseases (Lauzier et al., 2024). A cerebrovascular disease that may potentially benefit from such approaches is cerebral aneurysmal disease, which is currently treated primarily via endovascular or open surgical approaches, and currently has no disease-modifying medical therapies (Lauzier et al., 2022; Sekhar et al., 2024; Dallas et al., 2026).

Another important class of neurological diseases is neurodegenerative disease, which has numerous disease-modifying medical therapies currently used in the clinical setting, yet continues to inflict significant morbidity and mortality (Schwab et al., 2020; Valiukas et al., 2022). While many underlying drivers of neurodegenerative diseases and cerebral aneurysms are different, both involve an important inflammatory component in disease progression (Chyatte et al., 1999; Heneka et al., 2025). Indeed, imbalances in the populations of pro-inflammatory and anti-inflammatory immune effectors may underly disease progression in both classes of disease (Shao et al., 2017; Ma et al., 2024).

The various inflammatory or anti-inflammatory states of microglia and macrophages have garnered increased attention in the study of neuroimmunology (Murray and Wynn, 2011; Kapellos et al., 2019). This research has been supplemented by the identification and characterization of populations of brain-resident non-microglial macrophages known as border-associated macrophages (BAMs) (Vara-Perez and Movahedi, 2025). BAM populations include perivascular macrophages, choroid plexus macrophages, and meningeal macrophages (Silvin et al., 2023). Alongside microglia and peripheral monocyte-derived macrophages, BAMs can adopt varying inflammatory phenotypic states and complex expression profiles (Da Mesquita and Rua, 2024). The characterization of these macrophage populations has provided a new lens through which neurological disease targeting and modification can be approached. Other populations of immune cells have been observed through similar phenotypic classifications (Antuamwine et al., 2023).

In this work, we highlight the role of inflammation in both cerebral aneurysm and neurodegenerative disease, focusing our attention on immune phenotype imbalances. We concentrate our discussion of neurodegenerative diseases on Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), while cerebral aneurysms are understood to reflect the saccular morphology most frequently encountered in patients. We discuss the specific scenario of aneurysm rupture leading to subarachnoid hemorrhage (SAH), which is an upstream risk factor for the development of dementia, and provides the most conspicuous clinical link from cerebral aneurysms to neurodegeneration-like processes (Aydin and Peker, 2025). Finally, we describe the results of recent studies with pertinent therapeutic targeting.

Immune polarization and phenotypes

After monocytes infiltrate target tissues, the local signaling milieu induces various expression profiles in monocytes that then differentiate into macrophages (Munoz-Rojas et al., 2021; Tugal et al., 2013). Though a broad range of context-specific phenotypes can be adopted, macrophages can sometimes be classified as either “pro-inflammatory” or “anti-inflammatory.” A helpful paradigm for describing these expression profiles at a higher level is the “M1/M2” schema. In this classification system, classically activated “M1” macrophages can be induced by IFN-γ, TNF-α, or LPS, whereas alternatively activated “M2” macrophages can be induced by IL-4 and IL-10 (Orecchioni et al., 2019; Mills et al., 2000). The physiological and pathological role of each “state” of macrophages is distinct. “M1” phenotypes are involved in inflammation and produce reactive oxygen species, up-regulate tissue remodeling proteases, and produce additional pro-inflammatory cytokines (Chavez-Galan et al., 2015). Conversely, “M2” phenotypes can be viewed as counteracting the M1 influence, promoting tissue healing, secreting anti-inflammatory factors, and promoting angiogenesis (Mills et al., 2000). An analogous nomenclature is sometimes used for microglia (M1/M2), astrocytes (A1/A2), and in more limited contexts, neutrophils (N1/N2), though the latter is especially controversial (Deniset and Kubes, 2018). Similarly, the utility of the A1/A2 dichotomy is more appropriately applied as a way to facilitate the understanding of reactive astrocyte states in CNS diseases (Fan and Huo, 2021).

The schema of immune polarization is broadly controversial (Ransohoff, 2016). Indeed, these represent simplifications that reflect in-vitro conditions and do not fully describe the broad transcriptomic repertoire of each cell (Paolicelli et al., 2022; Escartin et al., 2021). In reality, intermediate or even indeterminate phenotypes are present in disease states. Macrophages, the original cell population in which polarization was defined, are best described via context-dependent approaches using transcriptomic analysis techniques (Qie et al., 2022). The use of the schemas of polarity is instead useful to discuss broad, disease-level macrotrends of pro- versus anti-inflammatory cell behavior by immune effectors. Such broadening of disease descriptions allows for parallels between cerebral aneurysm and neurodegenerative disease, which otherwise have limited links, to be feasible. In the current context, the framework is more appropriately applied to microglia and macrophages, compared to other effector populations. For identification of therapeutic targets or specific mechanisms of disease, specific cellular characterization is likely warranted.

Immune phenotypes in cerebral aneurysms

Though once considered to be congenital vessel dilations that worsen with age, saccular brain aneurysms are currently viewed as a downstream consequence of hemodynamic stress-induced inflammatory responses that cause primary vessel damage through degradation of vascular integrity (Signorelli et al., 2018). Histological studies have identified abundant inflammatory cell infiltration in cerebral aneurysms (Shimizu et al., 2019). Endoluminal vascular stress and turbulent blood flow activate the initial inflammation in the vessel wall leading to aneurysmal dilatation (Lauzier et al., 2024). This stress is responsible for the degradation of the internal elastic lamina and concurrent activation of inflammatory prostaglandin pathways in endothelial cells (Aoki et al., 2017). Local up-regulation of inflammatory cytokines results in the recruitment of circulating, blood-derived monocytes, which become macrophages once they infiltrate the vessel wall (Signorelli et al., 2018). Neutrophils may also be recruited at this stage (Ji et al., 2024). Once in the aneurysm wall, innate immune cells begin secreting IL-1β, IL-6, and TNF-α, promoting additional inflammation and subsequent vessel degradation (Shimizu et al., 2019; Aoki et al., 2009; Chalouhi et al., 2012). Of all immune cell populations, macrophages demonstrate the most pronounced infiltration in human cerebral aneurysms (Frosen et al., 2012; Chalouhi et al., 2013). Macrophages are likely important contributors to the growth and progression of brain aneurysms, as the number of macrophages present correlates with aneurysm size and growth (Shimizu et al., 2019).

A study suggest that inflammation is specifically driven by NF-kB in cerebral aneurysms, and is activated in macrophages localized in the adventitial and endothelial vessel layers, subsequently spreading throughout the entire vessel wall (Aoki et al., 2017). Pro-inflammatory functions are observed in this period of aneurysm development, with macrophages degrading the extracellular matrix through matrix metalloproteinase production, release of reactive oxygen species, and cytokine secretion into the local neurovascular milieu (Xu et al., 2019; Mitsui et al., 2020). Macrophage populations with anti-inflammatory phenotypes have also been observed in aneurysm walls (Lauzier et al., 2024). In general, “M1” and “M2” macrophages are present in similar proportions in unruptured brain aneurysms (Lauzier et al., 2024). A study found that ruptured aneurysms display elevated proportions of “M1” macrophages, therefore, periods of rapid growth leading to aneurysm rupture may be catalyzed by exaggerated inflammatory responses by macrophages themselves (Shan et al., 2021; Hasan et al., 2012). However, a more recent line of evidence suggests that an elevated M2/M1 ratio may be associated with intracranial aneurysm rupture (Stratilová et al., 2023). Another study performing single cell transcriptomic analyses in murine intracranial aneurysms identified six distinct monocyte/macrophage clusters with both pro- and anti-inflammatory features (Martinez et al., 2022). Therefore, confirmatory studies should be pursued using human tissue to identify corresponding monocyte/macrophage clusters.

Immune phenotypes in neurodegenerative diseases

Due to their niche in the brain parenchyma, microglia have a direct influence on other glial cells and neurons, in addition to their regulatory role as the “tissue resident” macrophage population of the brain. Pro-inflammatory microglia impair oligodendrocyte function and promote inflammatory astrocyte phenotypes, in addition to being neurotoxic (Colonna and Butovsky, 2017). Conversely, anti-inflammatory microglial phenotypes secrete anti-inflammatory cytokines, perform phagocytosis, and drive tissue-restorative activities including cerebral angiogenesis (Cao and He, 2013).

The balance of inflammatory states in neurodegenerative diseases has been an area of interest in recent investigations (Guo et al., 2022). Studies suggest that AD has an early peak of anti-inflammatory microglia phenotypes, coinciding with a stage of subclinical impairment or mild cognitive impairment, followed by a pro-inflammatory peak aligning with disease progression towards more significant clinical symptoms (Fan et al., 2017; Hamelin et al., 2016). The early anti-inflammatory effects of microglia are in part mediated by the receptor TREM2, a major cell surface receptor on microglia (Rayaprolu et al., 2013). Studies have demonstrated that TREM2 overexpression improves cognitive deficits, decreases Aβ plaque deposition, and reduces M1 pro-inflammatory response through a downstream JAK/STAT/SOCS signaling pathways (Rayaprolu et al., 2013; Hansen et al., 2018). As AD progresses, a buildup of toxic amyloid products continues, which accumulates, leading to neuronal stress, inflammatory microglial polarization, and an eventual decline in clinical status (Hansen et al., 2018). Microglial polarization is also induced via ERK activation, leading to a pro-inflammatory phenotype and secretion of inflammatory cytokines, thereby causing further neuronal damage (Hansen et al., 2018; Mass et al., 2017).

A transition from anti-inflammatory to pro-inflammatory microglia (or, broadly, “M2” to “M1”) has also been reported in PD and ALS (Liao et al., 2012; Tang and Le, 2016). Initially in PD, microglia are neuroprotective, and clear accumulated α-synuclein and tau proteins, reversing oxidative stress and functional impairment (Tian et al., 2026; Scheiblich et al., 2024). As PD progresses, aggregates of α-synuclein in dead or dying dopaminergic neurons may induce a shift towards M1 microglia via NADPH oxidase activation, which increases production of reactive oxygen species and inflammatory cytokines (Zhang et al., 2005). Likewise, in ALS, experimental studies in mice have also shown a shift from M2 to M1 microglial phenotype alongside disease progression (Tang and Le, 2016). An investigation in mSOD1 mutant mice observed this shift in tandem increased expression of nitric oxide synthase and NADPH oxidase, as well as pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 (Beers et al., 2008).

MS provides an opposite broad phenotypic shift with regards to timing. Indeed, there appears to be a restorative M1 to M2 transition, where M2 microglia can release neurotrophic molecules and anti-inflammatory cytokines as remyelination occurs (Miron et al., 2013). This transition towards remyelination was noted around 10 days after the onset of the lesion, coinciding with more Arg-1 CD68+ M2 cells than iNOS+ CD68+ M1 cells (Miron et al., 2013). Studies suggest that this change is mediated by activin-A, a member of the TGFβ superfamily which is also involved in oligodendrocyte differentiation (Miron et al., 2013).

While some populations of microglia promote conditions favoring anti-inflammatory signaling and remyelination, prolonged M2 polarization has been linked with unwanted fibrotic response and scarring under specific CNS conditions, which could exacerbate neural injury (David and Kroner, 2011). This underscores the importance of balancing pro- and anti-inflammatory activity in neurodegenerative diseases.

Communicating mechanisms

Aneurysmal inflammation and neurodegenerative diseases can produce a similar phenotype in the context of long-term cognitive impairment following aneurysmal SAH (Hoh et al., 2023). At the population level, a large cohort study conducted in Denmark identified an adjusted hazard ratio of 2.56 (95% CI, 2.28–2.88 in third adjusted model) for dementia after subarachnoid hemorrhage, identifying a potential relationship between the two neurological disorders (Corraini et al., 2017). There are some suggestions that delayed angiogenesis, persistent damage to capillary vessels, and chronic neuroinflammation may contribute to neurocognitive decline, though a definitive pathogenesis remains unclear (Francoeur and Mayer, 2016; Dodd et al., 2021). As the dementia following SAH is driven predominantly by vascular cognitive impairment, the overall etiology may be different, and simply produces a similar clinical phenotype. Current clinical data does not suggest that unruptured cerebral aneurysms increase the risk of developing dementia or other neurodegenerative diseases, as a 10-year observational study performed in Korea did not identify a significant difference in dementia when comparing treatment and observation for unruptured cerebral aneurysms (Han et al., 2024). This shifts the focus towards post-rupture pathological pathways. Shared vascular and systemic risk factors are known to contribute to both neurodegenerative disorders and aneurysm formation. Between the two, well-described common risk factors include hypertension, diabetes mellitus, smoking, obesity, and hypercholesterolemia (Karhunen et al., 2021; Senff et al., 2025). Hypertension, for instance, causes impaired cerebral blood flow autoregulation and microvessel disease, while advanced glycation end-products in diabetes lead to blood-brain-barrier damage (Fakih et al., 2022; Si et al., 2026; Lorenzini et al., 2024).

An additional line of evidence implicates thromboinflammation, a signaling axis linking coagulation and innate immune activation, as another pathway that may be shared between neurodegeneration and brain aneurysms (Wagner and Heger, 2022). After aneurysm rupture, thrombin generation, platelet activation, and microthrombosis amplify inflammatory signaling, in turn activating resident microglia and macrophages, and recruiting additional blood-derived leukocytes that potentially worsen brain injury (Geraghty et al., 2019). In animal models of AD and MS, the increased BBB permeability appears to allow fibrin to bind CD11b on microglia and macrophages, leading to neuroinflammatory signaling and oxidative damage that potentially exacerbate neurodegeneration (Mendiola et al., 2023; Merlini et al., 2019; Ryu et al., 2018).

Therapeutic approaches

Specific therapeutic targeting of macrophage polarization states with a target endpoint of shifting phenotypes from “M1” to “M2” (or vice-versa) have often failed due to oversimplifications produced by the dichotomous classification system (Ransohoff, 2016). Indeed, approaching polarization as a “switch” between states does not reflect in-vivo pathological conditions. Some studies have, however, targeted specific inflammatory signaling axes in immune effectors for cerebral aneurysms and/or neurodegenerative diseases, as discussed in the following.

In brain aneurysms, shifting the macrophage polarity ratio for tissue-resident macrophages appears to impact the likelihood of aneurysm progression and rupture (Hasan et al., 2012). Limited approaches have been employed in structural cerebrovascular lesions, but candidate agents include IL-10 DNA plasmid-based nanoparticles and other aptamers to broadly shift macrophage states have been suggested, though none are used clinically (Tardito et al., 2019; Muhammad et al., 2021). Cerebral aneurysms structurally affect a small portion of the overall cerebral vasculature, and targeted delivery to the disease site provides an additional challenge. Treatments have also been explored to modulate the inflammatory responses that underly neurodegenerative disorders, and in some cases, specifically target microglia. In AD, these include inhibiting NLRP3 inflammasome-associated proteins to dampen inflammatory microglial activity, promoting 5-HT2A antagonism to reduce amyloid plaque deposition by promoting Aβ plaque phagocytosis by anti-inflammatory microglia, and potential enhancement of TREM2 function on microglia (Park et al., 2019; Lu et al., 2021; Schlepckow et al., 2020). Parkinson’s disease is another neurodegenerative condition in which therapeutic agents have explored modulating neuroimmune inflammatory phenotypes. Therapeutic agents including vitamin D to promote M2-like microglial phenotypes, NLRP3 inhibitors to attenuate inflammation, and GLP-1 agonists to reduce both microglial activation and alpha synuclein aggregation have been piloted (Calvello et al., 2017; Zhang et al., 2019). Additional studies have explored microglial modulation as a therapeutic target in other neurodegenerative diseases (Gao et al., 2023). For instance, myeloperoxidase inhibition in multiple system atrophy suppressed microglial activation and decreased α-synuclein aggregation, while pharmacologic CB2 receptor agonism in patients with Huntington’s disease was found to reduce neuroinflammation and striatal neuron loss (Stefanova et al., 2012; Palazuelos et al., 2009). The aforementioned therapeutic modalities are summarized in Table 1.

Table 1. Summary of preclinical therapeutic agents.

Class of therapeutic agentProposed mechanismDisease of relevanceAnimal of studyStage of development
NLRP3 inhibitorsInhibits exogenous seeding of tau pathologyAlzheimer’s diseaseMousePreclinical
5-HT2A antagonistsReduces amyloid plaque deposition by promoting microglial Aβ phagocytosis and degradationAlzheimer’s diseaseMousePreclinical
TREM2-targeting antibodiesActivates TREM2Alzheimer’s diseaseMousePreclinical
Vitamin DInhibits microglial activation and promotes M2 polarization; protects dopaminergic neurons from inflammation and oxidative stressParkinson’s diseaseMousePreclinical and limited clinical
GLP-1 agonistsPrevents microglia-mediated astrocyte “polarization” to A1 neurotoxic phenotypeParkinson’s diseaseMousePreclinical
Myeloperoxidase inhibitorsSuppresses microglial activation and neuroinflammationMultiple System AtrophyMousePreclinical
CB2 agonistsReduces neuroinflammation and straital neuron lossHuntington’s diseaseMousePreclinical

Conclusion and future directions

Cerebral aneurysms and neurodegenerative disorders are driven by underlying neuroinflammatory processes. Microglia and macrophages in particular are integral to these processes, with immune functional state being a key factor in disease progression. Imbalances in immune phenotypic states can contribute to neurodegenerative disorders. Therapeutics targeting these mechanisms have been explored, but have met limited success and may require additional resource investment. This study is affected by the inherent limitations of cross-disease translational discussions, and transcriptomic work assessing profiles of aneurysmal tissue and neurodegenerative processes may provide more direct evidence for identifying shared pathways and therapeutic targets.

Generative AI statement

The author(s) declared that Generative AI was used in the creation of this manuscript. Our manuscript reflects our writing and our ideas obtained from the published literature. In limited contexts, AI tools were used. The primary use was in facilitating literature search and ensuring the most recent up-to-date literature was captured in our review to eliminate potential gaps.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes

Edited by: Brandon Peter Lucke-Wold, University of Florida, United States

Reviewed by: Alexandre Dias, Universidade do Porto, Portugal

Statements

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This work was in part supported by the UCLA Department of Pathology Translational Research Fund.

Data availability

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Author contributions

FL: Writing – original draft, Methodology, Resources, Writing – review & editing. DL: Methodology, Data curation, Conceptualization, Writing – review & editing, Supervision, Writing – original draft, Funding acquisition.

References

  1. Antuamwine B. B., Bosnjakovic R., Hofmann-Vega F., Wang X., Theodosiou T., Iliopoulos I.. (2023). N1 versus N2 and PMN-MDSC: a critical appraisal of current concepts on tumor-associated neutrophils and new directions for human oncology. Immunol. Rev. 314, 250 – 279. doi:, doi:10.1111/imr.13176
  2. Aoki T., Frosen J., Fukuda M., Bando K., Shioi G., Tsuji K.. (2017). Prostaglandin E2-EP2-NF-kappaB signaling in macrophages as a potential therapeutic target for intracranial aneurysms. Sci. Signal. 10. doi: doi:10.1126/scisignal.aah6037
  3. Aoki T., Kataoka H., Ishibashi R., Nozaki K., Egashira K., Hashimoto N. (2009). Impact of monocyte chemoattractant protein-1 deficiency on cerebral aneurysm formation. Stroke 40, 942 – 951. doi:, doi:10.1161/STROKEAHA.108.532556
  4. Aydin S., Peker S. (2025). Long-term cognitive decline after subarachnoid hemorrhage: pathophysiology, management, and future directions. Stroke 56, 1106 – 1111. doi:, doi:10.1161/STROKEAHA.124.049969
  5. Beers D. R., Henkel J. S., Zhao W., Wang J., Appel S. H. (2008). CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc. Natl. Acad. Sci. USA 105, 15558 – 15563. doi:, doi:10.1073/pnas.0807419105
  6. Bourque J., Hawiger D. (2021). Current and future immunotherapies for multiple sclerosis. Mo. Med. 118, 334 – 339.
  7. Calvello R., Cianciulli A., Nicolardi G., De Nuccio F., Giannotti L., Salvatore R.. (2017). Vitamin D treatment attenuates Neuroinflammation and dopaminergic neurodegeneration in an animal model of Parkinson's disease, shifting M1 to M2 microglia responses. J. Neuroimmune Pharmacol. 12, 327 – 339. doi:, doi:10.1007/s11481-016-9720-7
  8. Cao L., He C. (2013). Polarization of macrophages and microglia in inflammatory demyelination. Neurosci. Bull. 29, 189 – 198. doi:, doi:10.1007/s12264-013-1324-0
  9. Chalouhi N., Ali M. S., Jabbour P. M., Tjoumakaris S. I., Gonzalez L. F., Rosenwasser R. H.. (2012). Biology of intracranial aneurysms: role of inflammation. J. Cereb. Blood Flow Metab. 32, 1659 – 1676. doi:, doi:10.1038/jcbfm.2012.84
  10. Chalouhi N., Hoh B. L., Hasan D. (2013). Review of cerebral aneurysm formation, growth, and rupture. Stroke 44, 3613 – 3622. doi:, doi:10.1161/STROKEAHA.113.002390
  11. Chavez-Galan L., Olleros M. L., Vesin D., Garcia I. (2015). Much more than M1 and M2 macrophages, there are also CD169 (+) and TCR (+) macrophages. Front. Immunol. 6: 263. doi:, doi:10.3389/fimmu.2015.00263
  12. Chyatte D., Bruno G., Desai S., Todor D. R. (1999). Inflammation and intracranial aneurysms. Neurosurgery 45: 1146: 1137. doi:, doi:10.1097/00006123-199911000-00024
  13. Colonna M., Butovsky O. (2017). Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35, 441 – 468. doi:, doi:10.1146/annurev-immunol-051116-052358
  14. Corraini P., Henderson V. W., Ording A. G., Pedersen L., Horvath-Puho E., Sorensen H. T. (2017). Long-term risk of dementia among survivors of ischemic or hemorrhagic stroke. Stroke 48, 180 – 186. doi:, doi:10.1161/STROKEAHA.116.015242
  15. Da Mesquita S., Rua R. (2024). Brain border-associated macrophages: common denominators in infection, aging, and Alzheimer's disease? Trends Immunol. 45, 346 – 357. doi:, doi:10.1016/j.it.2024.03.007
  16. Dallas J., Lin M., Briggs R. G., Hopkins B. S., Ding L., Attenello F. J.. (2026). National Trends in the use of flow diversion for Management of Intracranial Aneurysms. Neurosurgery 99, 654 – 670. doi:, doi:10.1227/neu.0000000000003890
  17. David S., Kroner A. (2011). Repertoire of microglial and macrophage responses after spinal cord injury. Nat. Rev. Neurosci. 12, 388 – 399. doi:, doi:10.1038/nrn3053
  18. Deniset J. F., Kubes P. (2018). Neutrophil heterogeneity: bona fide subsets or polarization states? J. Leukoc. Biol. 103, 829 – 838. doi:, doi:10.1002/JLB.3RI0917-361R
  19. Dodd W. S., Laurent D., Dumont A. S., Hasan D. M., Jabbour P. M., Starke R. M.. (2021). Pathophysiology of delayed cerebral ischemia after subarachnoid hemorrhage: a review. J. Am. Heart Assoc. 10: e021845. doi:, doi:10.1161/JAHA.121.021845
  20. Escartin C., Galea E., Lakatos A., O'Callaghan J. P., Petzold G. C., Serrano-Pozo A.. (2021). Reactive astrocyte nomenclature, definitions, and future directions. Nat. Neurosci. 24, 312 – 325. doi: doi:10.1038/s41593-020-00783-4
  21. Fakih W., Zeitoun R., AlZaim I., Eid A. H., Kobeissy F., Abd-Elrahman K. S.. (2022). Early metabolic impairment as a contributor to neurodegenerative disease: mechanisms and potential pharmacological intervention. Obesity (Silver Spring) 30, 982 – 993. doi:, doi:10.1002/oby.23400
  22. Fan Z., Brooks D. J., Okello A., Edison P. (2017). An early and late peak in microglial activation in Alzheimer's disease trajectory. Brain 140, 792 – 803. doi:, doi:10.1093/brain/aww349
  23. Fan Y. Y., Huo J. (2021). A1/A2 astrocytes in central nervous system injuries and diseases: angels or devils? Neurochem. Int. 148: 105080. doi:, doi:10.1016/j.neuint.2021.105080
  24. Francoeur C. L., Mayer S. A. (2016). Management of delayed cerebral ischemia after subarachnoid hemorrhage. Crit. Care 20: 277. doi:, doi:10.1186/s13054-016-1447-6
  25. Frosen J., Tulamo R., Paetau A., Laaksamo E., Korja M., Laakso A.. (2012). Saccular intracranial aneurysm: pathology and mechanisms. Acta Neuropathol. 123, 773 – 786. doi:, doi:10.1007/s00401-011-0939-3
  26. Gao C., Jiang J., Tan Y., Chen S. (2023). Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets. Signal Transduct. Target. Ther. 8: 359. doi:, doi:10.1038/s41392-023-01588-0
  27. Geraghty J. R., Davis J. L., Testai F. D. (2019). Neuroinflammation and microvascular dysfunction after experimental subarachnoid hemorrhage: emerging components of early brain injury related to outcome. Neurocrit. Care. 31, 373 – 389. doi:, doi:10.1007/s12028-019-00710-x
  28. Golde T. E., Levey A. I. (2023). Immunotherapies for Alzheimer's disease. Science 382, 1242 – 1244. doi:, doi:10.1126/science.adj9255
  29. Guo S., Wang H., Yin Y. (2022). Microglia polarization from M1 to M2 in neurodegenerative diseases. Front. Aging Neurosci. 14: 815347. doi:, doi:10.3389/fnagi.2022.815347
  30. Hamelin L., Lagarde J., Dorothee G., Leroy C., Labit M., Comley R. A.. (2016). Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging. Brain 139: 26984188, 1252 – 1264. doi: doi:10.1093/brain/aww017
  31. Han H. J., Kim S., Kim J. J., Kim Y. B., Kim S. I., You S. C.. (2024). Association between preventive treatment for unruptured intracranial aneurysms and incident dementia: a nationwide population-based cohort study. Sci. Rep. 14: 24010. doi:, doi:10.1038/s41598-024-74054-8
  32. Hansen D. V., Hanson J. E., Sheng M. (2018). Microglia in Alzheimer's disease. J. Cell Biol. 217, 459 – 472. doi:, doi:10.1083/jcb.201709069
  33. Hasan D., Chalouhi N., Jabbour P., Hashimoto T. (2012). Macrophage imbalance (M1 vs. M2) and upregulation of mast cells in wall of ruptured human cerebral aneurysms: preliminary results. J. Neuroinflammation 9: 222. doi:, doi:10.1186/1742-2094-9-222
  34. Heneka M. T., van der Flier W. M., Jessen F., Hoozemanns J., Thal D. R., Boche D.. (2025). Neuroinflammation in Alzheimer disease. Nat. Rev. Immunol. 25, 321 – 352. doi:, doi:10.1038/s41577-024-01104-7
  35. Hoh B. L., Ko N. U., Amin-Hanjani S., Chou S.-Y., Cruz-Flores S., Dangayach N. S.. (2023). 2023 guideline for the management of patients with aneurysmal subarachnoid hemorrhage: a guideline from the American Heart Association/American Stroke Association. Stroke 54, e314 – e370. doi:, doi:10.1161/STR.0000000000000436
  36. Ji H., Han Y., Danyang J., Yue L., Hailan Y., Sun H.. (2024). Decoding the biology and clinical implication of neutrophils in intracranial aneurysm. Ann. Clin. Transl. Neurol. 11, 958 – 972. doi: doi:10.1002/acn3.52014
  37. Kapellos T. S., Bonaguro L., Gemund I., Reusch N., Saglam A., Hinkley E. R.. (2019). Human monocyte subsets and phenotypes in major chronic inflammatory diseases. Front. Immunol. 10: 2035. doi:, doi:10.3389/fimmu.2019.02035
  38. Karhunen V., Bakker M. K., Ruigrok Y. M., Gill D., Larsson S. C. (2021). Modifiable risk factors for intracranial aneurysm and aneurysmal subarachnoid hemorrhage: a Mendelian randomization study. J. Am. Heart Assoc. 10: e022277. doi:, doi:10.1161/JAHA.121.022277
  39. Lauzier D. C., Cler S. J., Vellimana A. K., Osbun J. W., Chatterjee A. R., Derdeyn C. P.. (2022). Evolution of elective intracranial aneurysm treatment. World Neurosurg. 168, 309 – 310. doi:, doi:10.1016/j.wneu.2022.08.133
  40. Lauzier D. C., Srienc A. I., Vellimana A. K., Dacey R. G. Jr., Zipfel G. J. (2024). Peripheral macrophages in the development and progression of structural cerebrovascular pathologies. J. Cereb. Blood Flow Metab. 44, 169 – 191. doi:, doi:10.1177/0271678X231217001
  41. Liao B., Zhao W., Beers D. R., Henkel J. S., Appel S. H. (2012). Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp. Neurol. 237, 147 – 152. doi:, doi:10.1016/j.expneurol.2012.06.011
  42. Lorenzini L., Maranzano A., Ingala S., Collij L. E., Tranfa M., Blennow K.. (2024). Association of vascular risk factors and cerebrovascular pathology with Alzheimer disease pathologic changes in individuals without dementia. Neurology 103: e209801. doi:, doi:10.1212/WNL.0000000000209801
  43. Lu J., Zhang C., Lv J., Zhu X., Jiang X., Lu W.. (2021). Antiallergic drug desloratadine as a selective antagonist of 5HT (2A) receptor ameliorates pathology of Alzheimer's disease model mice by improving microglial dysfunction. Aging Cell 20: e13286. doi:, doi:10.1111/acel.13286
  44. Ma H., Zhu M., Chen M., Li X., Feng X. (2024). The role of macrophage plasticity in neurodegenerative diseases. Biomark. Res. 12: 81. doi:, doi:10.1186/s40364-024-00624-7
  45. Martinez A. N., Tortelote G. G., Pascale C. L., McCormack I. G., Nordham K. D., Suder N. J.. (2022). Single-cell transcriptome analysis of the circle of Willis in a mouse cerebral aneurysm model. Stroke 53, 2647 – 2657. doi:, doi:10.1161/STROKEAHA.122.038776
  46. Mass E., Jacome-Galarza C. E., Blank T., Lazarov T., Durham B. H., Ozkaya N.. (2017). A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease. Nature 549, 389 – 393. doi:, doi:10.1038/nature23672
  47. Mendiola A. S., Yan Z., Dixit K., Johnson J. R., Bouhaddou M., Meyer-Franke A.. (2023). Defining blood-induced microglia functions in neurodegeneration through multiomic profiling. Nat. Immunol. 24, 1173 – 1187. doi:, doi:10.1038/s41590-023-01522-0
  48. Merlini M., Rafalski V. A., Rios Coronado P. E., Gill T. M., Ellisman M., Muthukumar G.. (2019). Fibrinogen induces microglia-mediated spine elimination and cognitive impairment in an Alzheimer's disease model. Neuron 101, 1099 – 1108. doi:, doi:10.1016/j.neuron.2019.01.014
  49. Mills C. D., Kincaid K., Alt J. M., Heilman M. J., Hill A. M. (2000). Pillars article: M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 199, 2194 – 2201. doi:, doi:10.4049/jimmunol.1701141
  50. Miron V. E., Boyd A., Zhao J. W., Yuen T. J., Ruckh J. M., Shadrach J. L.. (2013). M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211 – 1218. doi:, doi:10.1038/nn.3469
  51. Mitsui K., Ikedo T., Kamio Y., Furukawa H., Lawton M. T., Hashimoto T. (2020). TLR4 (toll-like receptor 4) mediates the development of intracranial aneurysm rupture. Hypertension 75, 468 – 476. doi:, doi:10.1161/HYPERTENSIONAHA.118.12595
  52. Muhammad S., Chaudhry S. R., Dobreva G., Lawton M. T., Niemela M., Hanggi D. (2021). Vascular macrophages as therapeutic targets to treat intracranial aneurysms. Front. Immunol. 12: 630381. doi:, doi:10.3389/fimmu.2021.630381
  53. Munoz-Rojas A. R., Kelsey I., Pappalardo J. L., Chen M., Miller-Jensen K. (2021). Co-stimulation with opposing macrophage polarization cues leads to orthogonal secretion programs in individual cells. Nat. Commun. 12: 301. doi:, doi:10.1038/s41467-020-20540-2
  54. Murray P. J., Wynn T. A. (2011). Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 11, 723 – 737. doi:, doi:10.1038/nri3073
  55. Orecchioni M., Ghosheh Y., Pramod A. B., Ley K. (2019). Macrophage polarization: different gene signatures in M1 (LPS+) vs. classically and M2 (LPS-) vs. alternatively activated macrophages. Front. Immunol. 10: 1084. doi:, doi:10.3389/fimmu.2019.01084
  56. Palazuelos J., Aguado T., Pazos M. R., Julien B., Carrasco C., Resel E.. (2009). Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity. Brain 132, 3152 – 3164. doi:, doi:10.1093/brain/awp239
  57. Paolicelli R. C., Sierra A., Stevens B., Tremblay M. E., Aguzzi A., Ajami B.. (2022). Microglia states and nomenclature: a field at its crossroads. Neuron 110, 3458 – 3483. doi:, doi:10.1016/j.neuron.2022.10.020
  58. Park M. H., Lee M., Nam G., Kim M., Kang J., Choi B. J.. (2019). N,N'-diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer's disease transgenic mice. Proc. Natl. Acad. Sci. USA 116, 23426 – 23436. doi:, doi:10.1073/pnas.1916318116
  59. Qie J., Liu Y., Wang Y., Zhang F., Qin Z., Tian S.. (2022). Integrated proteomic and transcriptomic landscape of macrophages in mouse tissues. Nat. Commun. 13: 7389. doi:, doi:10.1038/s41467-022-35095-7
  60. Ransohoff R. M. (2016). A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci. 19, 987 – 991. doi:, doi:10.1038/nn.4338
  61. Rayaprolu S., Mullen B., Baker M., Lynch T., Finger E., Seeley W. W.. (2013). TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. Mol. Neurodegener. 8: 19. doi:, doi:10.1186/1750-1326-8-19
  62. Ryu J. K., Rafalski V. A., Meyer-Franke A., Adams R. A., Poda S. B., Rios Coronado P. E.. (2018). Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat. Immunol. 19, 1212 – 1223. doi:, doi:10.1038/s41590-018-0232-x
  63. Salvarani C., Brown R. D. Jr., Calamia K. T., Christianson T. J., Weigand S. D., Miller D. V.. (2007). Primary central nervous system vasculitis: analysis of 101 patients. Ann. Neurol. 62, 442 – 451. doi:, doi:10.1002/ana.21226
  64. Scheiblich H., Eikens F., Wischhof L., Opitz S., Jungling K., Cserep C.. (2024). Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes. Neuron 112, 3106 – 3125. doi:, doi:10.1016/j.neuron.2024.06.029
  65. Schlepckow K., Monroe K. M., Kleinberger G., Cantuti-Castelvetri L., Parhizkar S., Xia D.. (2020). Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol. Med. 12: e11227. doi:, doi:10.15252/emmm.201911227
  66. Schwab A. D., Thurston M. J., Machhi J., Olson K. E., Namminga K. L., Gendelman H. E.. (2020). Immunotherapy for Parkinson's disease. Neurobiol. Dis. 137: 104760. doi:, doi:10.1016/j.nbd.2020.104760
  67. Sekhar L. N., Shenoy V. S., Sen R. D., Miller C. A., Montoure A., Ghodke B. V.. (2024). Current indications, trends, and long-term results of 233 bypasses to treat complex intracranial aneurysms: a location-specific analysis. Neurosurgery 95, 1106 – 1116. doi:, doi:10.1227/neu.0000000000003073
  68. Senff J., Tack R. W. P., Mallick A., Gutierrez-Martinez L., Duskin J., Kimball T. N.. (2025). Modifiable risk factors for stroke, dementia and late-life depression: a systematic review and DALY-weighted risk factors for a composite outcome. J. Neurol. Neurosurg. Psychiatry 96, 515 – 527. doi:, doi:10.1136/jnnp-2024-334925
  69. Shan D., Guo X., Yang G., He Z., Zhao R., Xue H.. (2021). Integrated transcriptional profiling analysis and immune-related risk model construction for intracranial aneurysm rupture. Front. Neurosci. 15: 613329. doi:, doi:10.3389/fnins.2021.613329
  70. Shao L., Qin X., Liu J., Jian Z., Xiong X., Liu R. (2017). Macrophage polarization in cerebral aneurysm: perspectives and potential targets. J. Immunol. Res. 2017, 1 – 7. doi:, doi:10.1155/2017/8160589
  71. Shimizu K., Kushamae M., Mizutani T., Aoki T. (2019). Intracranial aneurysm as a macrophage-mediated inflammatory disease. Neurol. Med. Chir. (Tokyo) 59, 126 – 132. doi:, doi:10.2176/nmc.st.2018-0326
  72. Si Z., Xiao B., Zhang M. (2026). Metabolic dysregulation in cerebral small vessel disease: pathogenesis and therapeutic targets. Neuroscience 599, 170 – 184. doi:, doi:10.1016/j.neuroscience.2026.02.021
  73. Signorelli F., Sela S., Gesualdo L., Chevrel S., Tollet F., Pailler-Mattei C.. (2018). Hemodynamic stress, inflammation, and intracranial aneurysm development and rupture: a systematic review. World Neurosurg. 115, 234 – 244. doi:, doi:10.1016/j.wneu.2018.04.143
  74. Silvin A., Qian J., Ginhoux F. (2023). Brain macrophage development, diversity and dysregulation in health and disease. Cell. Mol. Immunol. 20, 1277 – 1289. doi:, doi:10.1038/s41423-023-01053-6
  75. Stefanova N., Georgievska B., Eriksson H., Poewe W., Wenning G. K. (2012). Myeloperoxidase inhibition ameliorates multiple system atrophy-like degeneration in a transgenic mouse model. Neurotox. Res. 21, 393 – 404. doi:, doi:10.1007/s12640-011-9294-3
  76. Stratilová MH., Koblížek M., Štekláčová A., Beneš V., Sameš M., Hejčl A.. (2023). Increased macrophage M2/M1 ratio is associated with intracranial aneurysm rupture. Acta Neurochir (Wien). 165, 177 – 186. doi:, doi:10.1007/s00701-022-05418-0
  77. Tang Y., Le W. (2016). Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol. Neurobiol. 53, 1181 – 1194. doi:, doi:10.1007/s12035-014-9070-5
  78. Tardito S., Martinelli G., Soldano S., Paolino S., Pacini G., Patane M.. (2019). Macrophage M1/M2 polarization and rheumatoid arthritis: a systematic review. Autoimmun. Rev. 18: 102397. doi:, doi:10.1016/j.autrev.2019.102397
  79. Tian Z., Ji X., Liu J. (2022). Neuroinflammation in vascular cognitive impairment and dementia: current evidence, advances, and prospects. Int. J. Mol. Sci. 23: 23. doi:, doi:10.3390/ijms23116224
  80. Tian J., Liu X., Wang Z., Shi X., Dai C., Yang L. (2026). Microglia heterogeneity and therapeutic strategies in Parkinson's disease. Front. Immunol. 17: 1739341. doi:, doi:10.3389/fimmu.2026.1739341
  81. Tugal D., Liao X., Jain M. K. (2013). Transcriptional control of macrophage polarization. Arterioscler. Thromb. Vasc. Biol. 33, 1135 – 1144. doi:, doi:10.1161/ATVBAHA.113.301453
  82. Valiukas Z., Ephraim R., Tangalakis K., Davidson M., Apostolopoulos V., Feehan J. (2022). Immunotherapies for Alzheimer's disease-a review. Vaccines (Basel). 10: 10. doi:, doi:10.3390/vaccines10091527
  83. Vara-Perez M., Movahedi K. (2025). Border-associated macrophages as gatekeepers of brain homeostasis and immunity. Immunity 58, 1085 – 1100. doi:, doi:10.1016/j.immuni.2025.04.005
  84. Wagner D. D., Heger L. A. (2022). Thromboinflammation: from atherosclerosis to COVID-19. Arterioscler. Thromb. Vasc. Biol. 42, 1103 – 1112. doi:, doi:10.1161/ATVBAHA.122.317162
  85. Xu Z., Rui Y. N., Hagan J. P., Kim D. H. (2019). Intracranial aneurysms: pathology, genetics, and molecular mechanisms. NeuroMolecular Med. 21, 325 – 343. doi:, doi:10.1007/s12017-019-08537-7
  86. Zhang W., Wang T., Pei Z., Miller D. S., Wu X., Block M. L.. (2005). Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J. 19, 533 – 542. doi:, doi:10.1096/fj.04-2751com
  87. Zhang L., Zhang L., Li L., Holscher C. (2019). Semaglutide is neuroprotective and reduces alpha-Synuclein levels in the chronic MPTP mouse model of Parkinson's disease. J. Parkinsons Dis. 9, 157 – 171. doi:, doi:10.3233/JPD-181503

Citation

Lauzier, F. J. & Lauzier, D. C. (2026). Neuroimmune phenotypes in brain aneurysms and neurodegenerative diseases. Frontiers in Neuroscience, Volume 20. https://doi.org/
Received
Accepted
Published
Volume
20 - 2026

Copyright

Copyright © 2026 Lauzier and Lauzier.

License: https://creativecommons.org/licenses/by/4.0/

*Correspondence: David C. Lauzier

Article metrics

Views
0
Downloads
0
Citations
0
Shares
0

Related articles

RetractionRetraction: 17β-Estradiol protects neural stem/progenitor cells against ketamine-induced injury through estrogen receptor β pathwayFrontiers Editorial OfficeHypothesis and TheorySynchrony in neural and visceral systems: a bioelectric basis of consciousnessRavinder Jerath, Varsha MalaniCorrectionCorrection: Editorial: Unraveling the mechanisms of psychiatry disordersMaria Luisa Soto-Montenegro, Ana Carolina Pinheiro Campos, Diego Romero-Miguel