Introduction

Abstract

This issue of Immunological Reviews provides a comprehensive exploration of immune responses, cellular dynamics, and genetic factors influencing neurodegenerative and neuroinflammatory diseases, with an emphasis on Alzheimer's disease (AD) and other neurodegenerative disorders. Across seven chapters, leading researchers delve into various interconnected aspects of neuroimmunology. Topics include the gut microbiome's influence on AD through immune modulation and the role of neuroinflammation in compromising neuronal integrity. The contributions also cover central nervous system (CNS) macrophage functions in maintaining myelin health, the genetic basis and immune characteristics of Aicardi–Goutières Syndrome (AGS), and the centrality of apolipoprotein E (ApoE) in AD pathology. Each chapter brings new insights into how innate and adaptive immune responses influence both the progression and potential treatments of neurodegenerative conditions, focusing on mechanisms from genetic risk factors to environmental influences that shape disease trajectories.

What makes this issue especially intriguing is its multidisciplinary approach, merging insights from genetics, immunology, microbiology, and neurobiology to shed light on therapeutic possibilities. The exploration of prenatal influences on microglia, for instance, offers a fresh perspective on early-life risk factors for CNS diseases, while discussions on nucleic acid sensing reveal emerging connections between infection response and neurodegeneration. By presenting both current research and ongoing gaps in knowledge, the issue serves not only as an informative resource for scientists and clinicians but also as a stimulus for further studies aimed at discovering new treatments and interventions.

Tastan and Heneka review the complex role of neuroinflammation within the CNS, particularly focusing on how it influences neuronal integrity, structure, and functionality. Neuroinflammation is largely mediated by key CNS cells—such as microglia, astrocytes, pericytes, and infiltrated peripheral immune cells—whose activation contributes to neurodegenerative diseases. Neuroinflammation can be triggered by various factors, including infections, systemic inflammation, blood–brain barrier (BBB) disruption, and traumatic brain injuries. Once activated, these cellular responses lead to a cascade of events, including the release of pro-inflammatory cytokines, chemokines, and other molecules, resulting in a persistent inflammatory response within the CNS. Key mechanisms involved in neuroinflammation include pathogenic infections, systemic inflammation, and the activation of the NLRP3 inflammasome—a cellular complex involved in inflammation response. Disruption of the BBB is also a critical factor, as it permits the influx of peripheral immune cells, which exacerbate the inflammatory response within the CNS. Neuroinflammation impairs neuronal integrity through structural damage to synapses and axons, disruptions in calcium signaling, dysfunction in long-term potentiation, and broader alterations in brain networks. These changes not only affect neuronal structure but also significantly impair function, leading to cognitive dysfunction, memory impairment, and sensory disturbances. Additionally, mood disorders, cellular aging, and cellular senescence are associated with chronic neuroinflammation, emphasizing its widespread impact on neuronal functionality. Ultimately, Tastan and Heneka underscore the need to address knowledge gaps regarding neuroinflammation's role in CNS diseases and neuronal health. Future research into how neuroinflammatory pathways impact synaptic structures, neuronal signaling, and CNS network stability is essential for developing therapeutic approaches that may mitigate inflammation-related neurodegeneration and functional impairments.

Chandra and Vassar explore the potential role of gut microbiome (GMB)-derived metabolites in AD, highlighting a promising avenue for therapeutic strategies targeting the gut–brain axis. Recent studies have shown that the gut microbiome can significantly influence AD pathogenesis through the production of bioactive metabolites, which affect immune regulation and other physiological processes. This review focuses on key gut-derived metabolites, including short-chain fatty acids (SCFAs), bile acids (BAs), trimethylamine-N-oxide (TMAO), and pro-inflammatory byproducts like lipopolysaccharide (LPS), summarizing their respective impacts on AD-related processes and discussing the potential for therapeutic applications. SCFAs are bioactive compounds that have shown promise in preclinical studies as AD therapeutics when administered at optimal doses and timings. BAs, on the other hand, exhibit a more complex relationship with AD, as several BAs have been associated with disease progression, while others, such as tauroursodeoxycholic acid (TUDCA), show protective effects in AD mouse models. TMAO is generally viewed as detrimental, as elevated levels in AD patients correlate with biomarkers of AD pathology and exacerbate disease-related phenotypes in animal models. Similarly, elevated LPS levels in AD patients are associated with heightened neuroinflammation, amyloidosis, tauopathy, and cognitive decline. Therapeutic strategies aimed at reducing LPS or TMAO could therefore offer neuroprotective benefits in AD. Overall, the review emphasizes the need for continued investigation into the gut microbiome's influence on AD, particularly in the context of the gut–brain axis, to facilitate the development of effective GMB-targeted treatments. Modifying levels of these gut-derived metabolites could offer novel, non-invasive therapeutic options that harness the body's existing microbiome to combat neurodegenerative disease.

Lin and Holtzmann explore how ApoE influences AD, particularly through its effects on amyloid-β (Aβ) deposition, tau pathology, and the immune system's innate response. The review delves into ApoE's structural characteristics, its role in normal brain physiology, and its involvement in AD, focusing especially on immune regulation by microglia and astrocytes. ApoE, which exists in three primary isoforms—ApoE2, ApoE3, and ApoE4—has been shown to impact AD pathology significantly. The ApoE4 isoform is associated with a higher risk and accelerated progression of AD compared to ApoE2 and ApoE3. ApoE is predominantly produced by astrocytes under normal conditions, but in AD, its production is upregulated in reactive microglia and damaged neurons. ApoE influences lipid transport, neuronal repair, and modulates Aβ aggregation and clearance. Critically, APOE4 accelerates Aβ aggregation and deposition. Removing non-lipidated ApoE bound to Aβ or reducing ApoE expression can decrease amyloid burden in the brain, highlighting potential therapeutic strategies. Apart from Aβ, ApoE also plays a role in tau pathology. Tau proteins, when hyperphosphorylated, form neurofibrillary tangles. Similar to its impact on Aβ, the ApoE4 isoform exacerbates tau pathology and related neurodegeneration, whereas the absence of ApoE or reduction of ApoE levels can alleviate tau-related neurodegeneration. Another significant aspect of AD pathology associated with ApoE is cerebral amyloid angiopathy (CAA), which involves amyloid deposits in the walls of brain blood vessels, increasing the risk of microhemorrhages and brain edema. ApoE regulates CAA, with ApoE4 exacerbating amyloid deposition in blood vessels. ApoE depletion through gene knockout or immunotherapy can reduce CAA and its associated complications without triggering amyloid-related imaging abnormalities, thus presenting another promising therapeutic avenue. Beyond these pathological roles, ApoE affects the immune response in AD. ApoE is involved in regulating microglia and astrocyte activation. In AD, microglia and astrocytes respond to pathological changes by shifting into reactive states, which can either exacerbate or mitigate AD pathology. ApoE also affects T-cell activity, indicating a broader influence on immune regulation in AD. Ultimately, Lin and Holtzmann emphasize the need for further research into the complex interactions between ApoE isoforms, amyloid and tau pathology, and immune responses. Additionally, it suggests exploring therapeutic strategies targeting ApoE, particularly ApoE4, to modulate AD progression and reduce its pathological burden.

Hoffman and Miron examine the roles of different CNS macrophage populations in maintaining the myelin sheath surrounding neuronal axons. Myelin, produced by oligodendrocytes, is essential for efficient nerve impulse conduction and provides metabolic support to neurons. Myelin dysfunction, stemming from developmental issues, neurological diseases, or age-related degeneration, can lead to severe CNS impairments. This review explores the involvement of CNS macrophages—particularly microglia, border-associated macrophages (BAMs), and monocyte-derived macrophages—in the development, maintenance, and regeneration of myelin, along with their contributions to myelin pathology. Microglia have diverse and context-dependent roles. During white matter development, microglia clear out defective oligodendrocyte cells and excess myelin, ensuring proper myelin formation and preventing spontaneous demyelination. In adults, they serve as protective agents by maintaining oligodendrocyte stability and preventing hypermyelination. In cases of white matter damage, however, microglia may adopt a pro-inflammatory profile, contributing to demyelination through the release of inflammatory signals, though they can also assist in remyelination by clearing cellular debris, supporting the recycling of lipids, and releasing growth factors. Aging alters microglial function, often impairing their ability to phagocytize myelin debris and regulate lipid metabolism, which may increase susceptibility to neurodegenerative conditions. BAMs are another group of CNS macrophages that reside along the blood–brain barrier, vasculature, and other border regions within the CNS. These cells contribute indirectly to white matter health by preserving blood–brain barrier integrity and regulating cerebrospinal fluid flow. Their functions vary according to their molecular profiles; some BAM subsets are associated with lipid metabolism and phagocytosis, while others may influence immune responses by recruiting additional immune cells. BAMs that express the AD risk gene variant ApoE4 are associated with reactive oxygen species production and myelin loss, suggesting a potential link to neurodegenerative conditions. Monocyte-derived macrophages, which infiltrate the CNS during a brief postnatal period, are largely absent in healthy adult CNS but become prominent during demyelination and remyelination processes. These cells adopt a pro-inflammatory phenotype when myelin damage occurs, releasing signals that activate microglia and BAMs, and they can contribute to myelin loss through phagocytosis of damaged sheaths. However, during remyelination, monocytes transition to a regenerative state, marked by an anti-inflammatory profile that supports early-stage myelin repair. Together, these findings underscore the diverse and dynamic roles of CNS macrophages in myelin health. Understanding the unique contributions of each macrophage population could provide insights into potential therapeutic avenues for treating myelin-related diseases.

Stilman and colleagues explore how nucleic acid-sensing mechanisms traditionally associated with immune defense have roles in the CNS. Typically, these pathways detect pathogen-derived RNA and DNA to initiate immune responses, such as production of type I interferons (IFN-I, i.e., IFN-α and IFN-β), which combat infections. However, recent studies show that nucleic acid-sensing receptors in neurons and glial cells can also recognize self-derived nucleic acids, leading to unintended inflammatory responses that contribute to neurodegenerative diseases. Nucleic acid-sensing receptors function by identifying nucleic acids and initiating defense pathways through signaling proteins such as RIG-I, MDA5, and the cGAS-STING pathway, which are typically associated with pathogen defense but are now known to play roles in brain cells as well. Under normal conditions, neurons and glia utilize these pathways to maintain cellular health and development. For example, they help prevent the spread of infections by responding to RNA or DNA that enter cells abnormally. However, under conditions of cellular stress, self-derived nucleic acids can activate these pathways, leading to inflammation and damage to brain cells. In neurodegenerative diseases, these sensing pathways become dysregulated. Stilman and colleagues provide an overview of how nucleic acid sensing contributes to neurodegeneration, with mechanisms such as the release of mitochondrial DNA from damaged neurons and microglia, which activates the cGAS-STING pathway. This pathway produces inflammatory cytokines that exacerbate neuronal damage, creating a cycle of inflammation and cell death. In AD, amyloid plaques in the brain stimulate microglia to produce IFN-I, leading to chronic inflammation that can worsen disease progression. Another example is the involvement of Let-7 microRNAs, which promote neurodegeneration through mechanisms involving both cell-intrinsic and cell-extrinsic pathways. Apart from their roles in pathology, nucleic acid-sensing receptors also have regulatory roles in neuronal development and function. The review illustrates how specific toll-like receptors (TLRs) in neurons influence the development of neural circuits. For instance, TLR3 and TLR7 limit neurite outgrowth and neuronal morphology, which are critical to forming functional neural networks. Additionally, these receptors play a role in sensory neuron signaling; TLR7 and TLR3 activation in dorsal root ganglion neurons promote action potential firing, which is crucial for sensory processing. During brain development, nucleic acid-sensing pathways help ensure neural circuit integrity by removing damaged neurons. For example, TLR9 sensing DNA damage during development drives microglia to clear damaged neurons, allowing proper formation of sensory networks. Furthermore, nucleic acid sensing appears to support memory formation. In a process known as conditional fear conditioning, neurons in the hippocampus form DNA breaks, which TLR9 recognizes to facilitate synaptic remodeling needed for memory consolidation. Overall, Stilman and colleagues review presents nucleic acid sensing as a double-edged sword in the CNS. While it is crucial for defense and developmental regulation, its aberrant activation can lead to neuroinflammation and degeneration. Future research may help uncover ways to modulate these pathways to protect against neurodegenerative diseases.

Hofer and colleagues examine the Aicardi–Goutières Syndrome (AGS), a rare, genetic, autoinflammatory encephalopathy characterized by heightened IFN-I production due to mutations in genes that control antiviral responses and nucleic acid metabolism. AGS typically manifests in infancy or early childhood and progresses with a broad spectrum of neurological, dermatological, and systemic symptoms, including brain inflammation, skin lesions, and liver abnormalities. The root causes of AGS are genetic mutations that lead to the accumulation of nucleic acids or related hybrids in the cytoplasm. This triggers chronic production of IFN-α, setting off inflammatory cascades, and autocrine/paracrine signaling through the IFNAR receptor to induce gene expression changes associated with inflammation. The review covers key genes implicated in AGS, such as TREX1, RNaseH2, SAMHD1, ADAR1, and IFIH1, each of which contributes to abnormal nucleic acid accumulation or IFN-I pathway activation. In TREX1 mutations, cytoplasmic dsDNA accumulation leads to heightened IFN response, while RNaseH2 mutations result in RNA hybrid buildup. Similarly, SAMHD1 mutations allow cytoplasmic RNA hybrid accumulation, while loss of function in ADAR1 leads to the activation of dsRNA sensing pathways, especially through the Z-RNA binding protein ZBP1. Mutations in IFIH1—encoding MDA5—directly activate this IFN-I pathway. These genetic alterations, typically involving activation of cGAS-STING or MDA5-MAVS signaling, culminate in the phosphorylation and activation of TBK1, which drives interferon regulatory factor IRF3 and boosts IFN-α production. The chapter also discusses the clinical heterogeneity of AGS and its systemic impacts, particularly highlighting neurologic, dermatologic, and hepatic complications. A central focus is on preclinical models that replicate aspects of AGS for therapeutic research. Rodent models are extensively used, including mice with mutations in key AGS genes like TREX1, RNaseH2, SAMHD1, ADAR1, and IFIH1, as well as models with IFN-α overexpression. Additionally, non-rodent models and stem cell-derived models contribute to the understanding of AGS by simulating the multisystemic, progressive pathology of the disease. These models have illuminated many of the pathophysiological processes underlying AGS. Finally, the review discusses AGS gene expression data across various primary and stem-cell-derived human cell types, including those relevant to AGS pathology such as neurons and immune cells. These data reveal differential gene expression patterns that may inform cell-specific therapeutic targeting. Overall, Hofer and colleagues underscore the importance of developing comprehensive AGS models to deepen our understanding of autoinflammatory mechanisms and refine potential treatments aimed at mitigating the excessive IFN-I response in AGS.

Tagliatti and colleagues delve into the impact of prenatal environmental stressors on microglia. Emerging research indicates that adverse prenatal conditions, such as maternal infections, malnutrition, high-fat diets, and sleep disturbances, significantly increase the likelihood of neurodevelopmental issues in offspring. Tagliatti and colleagues summarize current findings on how these prenatal stressors reprogram microglia, potentially making them more vulnerable to dysregulation later in life, with implications for neurodevelopmental and psychiatric disorders. One of the primary prenatal stressors affecting microglia is maternal infection, often referred to as maternal immune activation (MIA). MIA models have provided substantial insights into how prenatal infections alter microglia in offspring. Studies show that MIA leads to specific transcriptomic and proteomic changes in microglia, which affect their responsiveness to later stressors. These molecular changes often shift microglia from a resting state to an activated state. This state, when induced early, can make offspring more susceptible to neurodevelopmental disorders such as autism and schizophrenia. Maternal malnutrition, including high-fat diet, represents another significant risk factor for altering microglial development. Nutritional deficiencies during pregnancy can reprogram microglia's responsiveness to inflammation, creating a heightened state of reactivity that persists into adulthood. This altered microglial state has been associated with increased inflammation, impaired synaptic pruning, and altered neurogenesis in animal models, contributing to long-term cognitive and emotional challenges in offspring. Such findings underscore the importance of maternal diet on fetal brain health, suggesting that a balanced nutritional intake during pregnancy can help mitigate these adverse effects. Sleep deprivation during pregnancy is also emerging as a potential stressor that affects microglia. Current findings suggest that sleep deprivation in expectant mothers might serve as a general stressor that activates microglia, but it remains unclear whether this activation follows specific molecular pathways. The implications of maternal sleep loss on offspring brain development are still being explored, particularly concerning whether it induces chronic activation of microglia or temporary changes that resolve over time. Tagliatti and colleagues also highlight the role of sex differences in microglial responses to maternal stressors. Male and female offspring often exhibit different patterns of microglial activation following prenatal stress, possibly due to variations in sex hormones. These differences may influence vulnerability to certain disorders; for instance, males may be more susceptible to conditions like autism spectrum disorder, while females may face higher risks of depression or anxiety. Exploring these sex-based differences could guide future therapeutic approaches to manage or mitigate these risks. Finally, the review of Tagliatti and colleagues calls for further research on the paternal contributions to offspring microglia vulnerability, as recent studies hint at the potential influence of paternal health and lifestyle on offspring neurodevelopment. While maternal factors have traditionally been the focus, the possible paternal impact on microglia maturation and function remains largely uncharted.

In summary, the reviews in this issue of Immunological Reviews collectively underscore the intricate interplay between the immune system and neurodegenerative diseases, offering novel insights and highlighting the critical need for further research in neuroimmunology. As we move forward, the potential for new therapeutic interventions targeting immune pathways in neurodegenerative diseases becomes increasingly apparent. These contributions promise to illuminate pathways for innovative treatments that address the underlying immunological factors contributing to neurodegeneration.

The author declares no conflicts of interest.