# 文献综述示例｜Protective mechanisms of myeloid-derived monocytes and macrophages in neurodegenerative diseases

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**主题**: Protective Mechanisms Myeloid-Derived Monocytes/Macrophages Neurodegenerative Diseases
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# Myeloid-Derived Monocytes and Macrophages in Neurodegenerative Diseases: Protective Mechanisms and Therapeutic Implications

> Abstract: Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss accompanied by complex neuroinflammatory responses. Myeloid-derived cells, particularly microglia and infiltrating monocytes/macrophages, occupy a central position in these processes, exhibiting remarkable phenotypic plasticity that enables both neuroprotective and neurotoxic functions. This review synthesizes current understanding of the protective mechanisms employed by myeloid cells in neurodegeneration, encompassing phagocytic clearance of pathological protein aggregates, trophic factor secretion, metabolic reprogramming, and intercellular communication via extracellular vesicles. We examine how microglia transition between homeostatic and disease-associated states, how infiltrating monocytes contribute to lesion containment and tissue repair, and how myeloid cells interface with the gut-brain axis and systemic immunity. The dual nature of myeloid responses, wherein protective functions can become maladaptive with disease progression or chronic stimulation, presents both challenges and opportunities for therapeutic intervention. We critically evaluate evidence from human studies, animal models, and emerging single-cell analyses, highlighting inconsistencies and knowledge gaps. Understanding the context-dependent protective mechanisms of myeloid cells may inform strategies to harness their reparative capacity while mitigating detrimental inflammation in neurodegenerative disease.

## Introduction

The central nervous system was long regarded as immunologically privileged, shielded from peripheral immune surveillance by the blood-brain barrier and lacking conventional lymphatic drainage. This view has been substantially revised over the past two decades. The brain harbors a diverse population of resident myeloid cells, most prominently microglia, which arise from yolk sac progenitors and maintain themselves through local proliferation independent of bone marrow contribution [#34]. Beyond these resident populations, the discovery of functional meningeal lymphatic vessels and the characterization of glymphatic clearance pathways have revealed dynamic interfaces between the CNS and peripheral immune system [#116]. Monocyte-derived macrophages can infiltrate the brain parenchyma under pathological conditions, and their contributions to disease progression or resolution remain actively debated [#59].

Neurodegenerative diseases share common features of protein misfolding and aggregation, synaptic dysfunction, and progressive neuronal loss, yet each disorder exhibits distinct pathological hallmarks and affected neural circuits [#6]. Alzheimer's disease is defined by extracellular amyloid-beta plaques and intracellular tau neurofibrillary tangles, while Parkinson's disease features alpha-synuclein-containing Lewy bodies predominantly in dopaminergic neurons of the substantia nigra [#12, #99]. The observation that neuroinflammation accompanies essentially all neurodegenerative conditions, often preceding overt neuronal loss, has shifted attention toward immune mechanisms as potential drivers rather than mere consequences of disease [#6, #48]. Microglial activation is consistently detected in affected brain regions across Alzheimer's disease, Parkinson's disease, and other proteinopathies, and genome-wide association studies have identified numerous risk loci in genes expressed predominantly by myeloid cells, including TREM2, CD33, and others involved in phagocytosis and lipid metabolism [#8, #98].

The concept of neuroprotection by myeloid cells rests on several pillars. Microglia continuously survey the brain parenchyma, phagocytose debris and protein aggregates, and secrete factors that support neuronal function and synaptic plasticity [#8, #23]. Under acute injury conditions, infiltrating monocytes can contribute to lesion containment and promote repair. However, the same cells can adopt phenotypes that exacerbate pathology, secreting pro-inflammatory cytokines, generating reactive oxygen species, and contributing to synaptic stripping [#6, #42]. This functional duality complicates therapeutic strategies aimed at simply suppressing or enhancing myeloid responses. The challenge lies in understanding the molecular determinants that govern protective versus detrimental outcomes and identifying windows of opportunity for intervention.

This review examines protective mechanisms of myeloid-derived monocytes and macrophages in neurodegenerative diseases. We consider evidence from human neuropathological studies, animal models, and emerging technologies including single-cell transcriptomics and lineage tracing. We address how myeloid cells recognize and clear pathological proteins, how their metabolic states influence effector functions, and how they communicate with other cell types in the CNS and periphery. Throughout, we emphasize inconsistencies in the literature and unresolved questions, particularly regarding the translatability of findings from rodent models to human disease.

## Microglia: Guardians and Threats in the Diseased Brain

Microglia constitute approximately 5-10% of cells in the adult brain and perform essential homeostatic functions that extend well beyond classical immune roles [#23, #34]. Under steady-state conditions, microglia continuously extend and retract processes to survey their environment, contact synaptic elements, and respond rapidly to perturbations. They phagocytose apoptotic cells, synaptic material, and myelin debris, and secrete factors including brain-derived neurotrophic factor that support neuronal survival and plasticity [#8, #40]. The homeostatic microglial phenotype is maintained through local cues, including neuronal-derived factors such as CX3CL1 acting on microglial CX3CR1, and CD200-CD200R interactions that restrain excessive activation [#23].

In neurodegenerative disease, microglia undergo dramatic phenotypic changes. Single-cell RNA sequencing studies have identified multiple microglial states in Alzheimer's disease brain tissue, including a disease-associated microglia (DAM) population characterized by upregulation of phagocytic and lipid metabolism genes such as TREM2, APOE, and CST7 [#8, #47]. These DAM cells localize near amyloid plaques and appear to represent an attempt to contain and clear pathological protein deposits. The identification of TREM2 as a risk gene for late-onset Alzheimer's disease has focused attention on the phagocytic functions of microglia, as TREM2 signaling promotes uptake of amyloid-beta and apoptotic neurons [#8, #72]. Loss-of-function TREM2 variants impair this clearance capacity and are associated with accelerated disease progression.

The relationship between microglial activation states and disease outcomes is not straightforward. While some degree of microglial reactivity appears protective, particularly in early disease stages when phagocytic clearance can limit protein accumulation, sustained or excessive activation contributes to neurodegeneration through multiple mechanisms [#6, #48]. Activated microglia release pro-inflammatory cytokines including TNF-alpha, IL-1beta, and IL-6, generate reactive oxygen and nitrogen species, and can induce neurotoxic astrocytic responses through secretion of IL-1alpha, TNF-alpha, and C1q [#63]. The concept of microglial heterogeneity has been refined by observations that distinct activation states coexist within the same brain region and shift with disease progression [#8, #70]. This temporal and spatial complexity challenges binary classifications of microglia as either M1-like (pro-inflammatory) or M2-like (anti-inflammatory), a framework originally derived from in vitro studies that has proven inadequate for capturing the diversity of microglial states in vivo [#23, #113].

The protective functions of microglia in proteinopathies extend beyond phagocytosis. Microglia secrete proteases including insulin-degrading enzyme and neprilysin that can degrade extracellular amyloid-beta [#8]. They also contribute to the formation of physical barriers around amyloid plaques, compacting fibrillar material into dense cores that may sequester more toxic soluble species [#108]. In Parkinson's disease models, microglia can internalize and degrade alpha-synuclein, and their efficiency in doing so influences the spread of pathology between brain regions [#99, #104]. However, the phagocytic capacity of microglia declines with age and in the context of chronic disease, partly due to impairments in lysosomal function and autophagy [#7, #78]. This age-related decline in clearance capacity may represent a critical juncture where protective microglial functions fail and pathology progresses.

## Monocyte-Derived Macrophages: Infiltrators with Dual Roles

The contribution of bone marrow-derived monocytes to the brain myeloid pool in neurodegenerative disease remains controversial. Under physiological conditions, the blood-brain barrier restricts monocyte entry, and resident microglia are sufficient for most CNS immune functions [#34]. However, in disease states associated with blood-brain barrier disruption or neuroinflammation, monocytes can infiltrate the brain parenchyma and perivascular spaces [#28, #59]. The extent of this infiltration and its functional significance vary across diseases and models.

In experimental autoimmune encephalomyelitis, a model of multiple sclerosis, monocyte-derived macrophages are clearly pathogenic, contributing to demyelination and axonal injury [#120]. Their role in Alzheimer's disease and Parkinson's disease is less clear. Some studies using bone marrow chimeras and parabiosis models have reported substantial monocyte contribution to amyloid plaque-associated myeloid populations, while others have found minimal infiltration under steady-state conditions [#59]. These discrepancies may reflect differences in disease models, mouse strains, and the methods used to distinguish resident microglia from infiltrating monocytes. The development of fate-mapping approaches using tamoxifen-inducible CX3CR1-CreER mice has enabled more precise discrimination, and recent studies suggest that monocyte infiltration is limited in most Alzheimer's disease models unless there is concurrent vascular pathology [#98].

When monocytes do infiltrate the diseased brain, their functions appear context-dependent. In acute injury models such as ischemic stroke, monocyte-derived macrophages contribute to debris clearance and tissue repair, promoting angiogenesis and axonal sprouting [#18, #52]. In chronic neurodegenerative conditions, infiltrating cells may adopt phenotypes that either complement or antagonize resident microglial functions. Single-cell analyses of Alzheimer's disease brain tissue have identified macrophage populations expressing markers of both microglia and peripheral monocytes, suggesting intermediate states that are difficult to classify [#47, #98]. The chemokine receptors CCR2 and CX3CR1 differentially mark monocyte subsets, and their ligands are upregulated in neurodegenerative conditions, providing potential routes for monocyte recruitment [#35].

The therapeutic potential of modulating monocyte infiltration has been explored in several contexts. Enhancing CCR2-mediated recruitment of inflammatory monocytes has been shown to exacerbate pathology in some Alzheimer's disease models, while blocking this pathway can reduce amyloid burden [#59]. Conversely, promoting the infiltration of specific monocyte subsets with reparative phenotypes has been proposed as a therapeutic strategy, though achieving this selectively remains challenging. The development of monocyte-based cell therapies, in which autologous cells are polarized ex vivo and adoptively transferred, represents an active area of investigation [#13, #27].

## Phagocytic Clearance of Pathological Proteins

The phagocytic removal of protein aggregates represents a primary protective mechanism of myeloid cells in neurodegeneration. Microglia recognize amyloid-beta through multiple receptors, including TREM2, CD36, scavenger receptors, and Toll-like receptors [#8, #107]. Engagement of these receptors triggers internalization and delivery to the endolysosomal pathway, where amyloid-beta is degraded by cathepsins and other proteases [#78]. The efficiency of this process is influenced by the aggregation state of amyloid-beta, with fibrillar forms being more readily phagocytosed than soluble oligomers, which are thought to be the most neurotoxic species [#108].

TREM2 has emerged as a critical regulator of microglial phagocytosis and metabolism. TREM2 signaling through DAP12 activates Syk and PI3K pathways, promoting cytoskeletal reorganization and phagosome formation [#72]. TREM2 also supports microglial survival and proliferation, particularly in the context of amyloid pathology. Human genetic studies have established that the R47H variant of TREM2, which impairs ligand binding, increases Alzheimer's disease risk approximately threefold [#8, #98]. Mouse models carrying this variant or lacking TREM2 entirely show reduced microglial clustering around amyloid plaques, impaired plaque compaction, and altered disease progression [#72]. However, the effects of TREM2 deficiency on amyloid burden are complex, with some studies reporting increased plaque load and others finding no change or even reduced pathology, depending on the disease stage examined [#8].

The phagocytic clearance of alpha-synuclein in Parkinson's disease has received less attention but is equally important. Microglia can internalize both monomeric and fibrillar alpha-synuclein, and this uptake can trigger either protective degradation or pro-inflammatory responses depending on the context [#99, #104]. Toll-like receptors, particularly TLR2 and TLR4, have been implicated in sensing extracellular alpha-synuclein and initiating inflammatory signaling [#104, #107]. The balance between phagocytic clearance and inflammatory activation may determine whether microglial responses to alpha-synuclein are beneficial or detrimental. In this context, the observation that alpha-synuclein pathology spreads between brain regions in a prion-like manner raises the question of whether microglia limit or facilitate this spread [#99]. Some evidence suggests that microglia can degrade internalized alpha-synuclein and thereby restrict propagation, while other studies indicate that microglia may release undigested fibrils that seed pathology in neighboring cells.

Beyond protein aggregates, myeloid cells phagocytose dying neurons, synaptic elements, and myelin debris. The clearance of apoptotic cells, termed efferocytosis, is essential for preventing secondary necrosis and limiting inflammation [#75]. Microglia recognize phosphatidylserine exposed on apoptotic cell surfaces through receptors including TREM2, MerTK, and integrins. Impaired efferocytosis in aging and disease may contribute to the accumulation of cellular debris that fuels chronic inflammation [#9, #16]. Similarly, the phagocytosis of damaged synapses, while potentially contributing to synaptic loss in disease, may also represent a homeostatic mechanism for removing dysfunctional elements and promoting circuit remodeling [#23].

## Metabolic Reprogramming and Myeloid Cell Function

Cellular metabolism fundamentally shapes macrophage and microglial phenotypes, and metabolic reprogramming has emerged as a central mechanism controlling protective versus detrimental functions [#49, #80, #117]. In vitro studies have established that pro-inflammatory (M1-like) macrophages rely heavily on glycolysis, while anti-inflammatory (M2-like) macrophages utilize oxidative phosphorylation and fatty acid oxidation [#113]. This dichotomy, while oversimplified, has provided a framework for understanding how metabolic states influence effector functions.

In the context of neurodegeneration, microglial metabolism is dynamically regulated by the local environment. Amyloid-beta engagement triggers metabolic changes that support phagocytosis and inflammatory signaling, including increased glucose uptake and glycolysis [#117]. The transcription factor HIF-1alpha, which coordinates glycolytic gene expression, is stabilized under conditions of inflammation and may promote microglial activation [#53]. However, sustained glycolytic metabolism can lead to mitochondrial dysfunction and oxidative stress, potentially contributing to microglial senescence and impaired function [#29, #86].

Lipid metabolism is particularly relevant to microglial function in Alzheimer's disease, given the strong genetic association of lipid-related genes with disease risk. APOE, the strongest genetic risk factor for late-onset Alzheimer's disease, is primarily expressed by microglia and astrocytes in the brain [#47, #98]. The APOE4 isoform, which increases disease risk, is associated with altered lipid droplet accumulation in microglia. A recent study using single-nucleus RNA sequencing identified a microglial state defined by expression of ACSL1, an enzyme involved in lipid droplet formation, that was most abundant in Alzheimer's disease patients with the APOE4/4 genotype [#47]. In human iPSC-derived microglia, fibrillar amyloid-beta induced ACSL1 expression and lipid droplet accumulation, and this effect was exacerbated in APOE4-carrying cells. These lipid-laden microglia exhibited impaired phagocytic function and increased secretion of inflammatory mediators, suggesting that dysregulated lipid metabolism may compromise protective microglial functions.

The amino acid metabolism of myeloid cells also influences their functions in neurodegeneration. Arginine metabolism through inducible nitric oxide synthase generates nitric oxide, a key effector molecule in antimicrobial defense that can also cause oxidative damage when produced in excess [#113]. Alternatively, arginine metabolism through arginase generates polyamines that support cell proliferation and tissue repair. The balance between these pathways is regulated by cytokines and other environmental cues. Tryptophan metabolism through indoleamine 2,3-dioxygenase generates kynurenine derivatives that can have neuroactive properties, and this pathway has been implicated in both neuroprotection and neurodegeneration depending on the downstream metabolites produced [#115].

Mitochondrial function and dynamics are increasingly recognized as determinants of myeloid cell phenotype and viability. Damaged mitochondria release reactive oxygen species and mitochondrial DNA, which can activate inflammatory signaling through the cGAS-STING pathway and NLRP3 inflammasome [#29, #81]. Mitophagy, the selective autophagic removal of damaged mitochondria, is essential for maintaining mitochondrial quality and preventing excessive inflammation [#7, #29]. Impaired mitophagy in aging microglia may contribute to the chronic low-grade inflammation characteristic of the aged brain [#9, #16]. Intercellular transfer of mitochondria from mesenchymal stem cells or other donor cells to damaged neurons has been proposed as a therapeutic strategy, though the extent to which this occurs endogenously in neurodegenerative disease remains unclear [#65].

## Inflammasome Signaling and Pyroptosis in Myeloid Cells

The NLRP3 inflammasome has emerged as a central mediator of neuroinflammation in neurodegenerative diseases [#19, #57, #118]. NLRP3 is expressed primarily in myeloid cells, where it assembles into a multiprotein complex in response to various danger signals, leading to activation of caspase-1 and cleavage of pro-IL-1beta and pro-IL-18 into their mature forms [#19, #118]. Caspase-1 also cleaves gasdermin D, generating an N-terminal fragment that forms pores in the plasma membrane, leading to pyroptosis, a lytic and inflammatory form of cell death [#30, #73, #92].

In Alzheimer's disease, amyloid-beta has been shown to activate the NLRP3 inflammasome in microglia, and this activation contributes to pathology in mouse models. NLRP3-deficient mice crossed with APP/PS1 amyloid model mice show reduced amyloid deposition, decreased neuroinflammation, and improved cognitive function [#118]. Similarly, inhibition of caspase-1 or IL-1beta signaling ameliorates pathology in these models. The mechanism by which NLRP3 activation promotes amyloid pathology may involve impaired phagocytic function, as inflammasome activation can divert cellular resources away from clearance mechanisms and induce pyroptosis of microglia, reducing the available phagocytic pool [#19, #118].

In Parkinson's disease, alpha-synuclein fibrils activate the NLRP3 inflammasome in microglia, and this activation contributes to dopaminergic neuron loss in mouse models [#104, #118]. Fibrillar alpha-synuclein is taken up by microglia through phagocytosis, and its accumulation in the cytosol triggers inflammasome assembly. The release of IL-1beta and other inflammatory mediators then acts on neurons and other glial cells to promote neurodegeneration. Blocking NLRP3 activation or IL-1 receptor signaling has shown protective effects in Parkinson's disease models, supporting the pathogenic role of this pathway [#24, #83].

The therapeutic targeting of NLRP3 has attracted considerable interest, with several small molecule inhibitors in development [#24, #83]. These compounds target various components of the inflammasome pathway, including NLRP3 itself, caspase-1, and gasdermin D. While preclinical studies have shown promising results in models of Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions, clinical translation has been challenging. The specificity of some inhibitors has been questioned, and the long-term consequences of suppressing inflammasome signaling in the brain are not fully understood [#24]. Moreover, the NLRP3 inflammasome also serves protective functions in host defense, and its chronic inhibition could increase susceptibility to infection [#19, #57].

Pyroptosis of myeloid cells themselves may have dual consequences in neurodegeneration. On one hand, pyroptosis eliminates cells that are contributing to detrimental inflammation, potentially limiting tissue damage. On the other hand, pyroptosis releases cellular contents, including damage-associated molecular patterns, that can amplify inflammatory responses and recruit additional immune cells [#30, #73, #92]. The net effect of myeloid pyroptosis in neurodegenerative disease likely depends on the context and timing. Gasdermin D inhibitors that block pyroptosis without affecting inflammasome-dependent cytokine processing have been proposed as a more targeted approach, though their efficacy in neurodegenerative disease models remains to be established [#24, #73].

## Trophic Factor Secretion and Neuronal Support

Beyond their roles in phagocytosis and inflammation, myeloid cells support neuronal function through the secretion of trophic factors. Microglia produce brain-derived neurotrophic factor (BDNF), which is critical for synaptic plasticity, learning, and memory [#40]. BDNF signaling through TrkB receptors promotes neuronal survival, dendritic arborization, and synaptic strengthening. In Alzheimer's disease, BDNF levels are reduced in the brain, and this reduction correlates with cognitive decline [#40]. Whether microglial BDNF production is impaired in disease or whether the overall reduction reflects neuronal loss is not entirely clear, but enhancing microglial BDNF secretion has been proposed as a therapeutic strategy.

Microglia also produce other neurotrophic factors, including insulin-like growth factor 1 (IGF-1), glial cell line-derived neurotrophic factor (GDNF), and fibroblast growth factor 2 (FGF2) [#8]. These factors support neuronal survival and function through distinct receptor systems. The regulation of trophic factor secretion by microglia is influenced by their activation state, with some factors being produced preferentially by homeostatic or anti-inflammatory microglia. The concept that microglia can be therapeutically redirected toward a trophic-supportive phenotype has motivated studies of various pharmacological agents, including those that activate nuclear receptors such as PPAR-gamma or liver X receptors [#8, #42].

The interaction between microglia and synapses extends beyond trophic support. Microglia participate in synaptic pruning during development, eliminating excess synapses through complement-dependent phagocytosis [#23]. In the adult brain, microglia continue to survey and modify synapses, and this process is dysregulated in neurodegenerative disease. Excessive synaptic pruning by activated microglia may contribute to the synaptic loss that precedes neuronal death in Alzheimer's disease and other conditions [#6, #42]. Conversely, microglial support of synaptic plasticity through BDNF and other factors is essential for learning and memory. The balance between synaptic elimination and support is likely regulated by neuronal activity and the local cytokine environment.

Astrocytes, the most abundant glial cell type, interact extensively with microglia and are also targets of myeloid-derived signals [#42, #60]. Reactive astrocytes can adopt neurotoxic phenotypes when exposed to microglial-derived IL-1alpha, TNF-alpha, and C1q [#63]. This astrocytic conversion has been implicated in the progression of various neurodegenerative diseases. Conversely, astrocytes can support microglial functions through the secretion of factors that promote phagocytosis and limit inflammation. The bidirectional communication between microglia and astrocytes is an important determinant of the overall glial response in neurodegeneration [#42, #60].

## Extracellular Vesicles and Intercellular Communication

Extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as important mediators of cell-to-cell communication in the CNS [#10, #66]. Myeloid cells release EVs that carry proteins, lipids, and nucleic acids, and these vesicles can influence the function of recipient cells, including neurons, astrocytes, and other immune cells. In the context of neurodegeneration, microglial EVs have been shown to contain amyloid-beta, alpha-synuclein, and other pathological proteins, and their release may contribute to the spread of pathology between brain regions [#10, #66].

The protective functions of myeloid EVs are less well characterized but potentially significant. Microglia release EVs containing enzymes that can degrade amyloid-beta, and these EVs may contribute to extracellular clearance of pathological proteins [#10]. EVs from anti-inflammatory macrophages have been shown to promote neuronal survival and reduce inflammation in models of brain injury [#27, #82]. The therapeutic potential of EVs derived from mesenchymal stem cells or polarized macrophages is being actively explored, with some studies reporting beneficial effects in models of stroke, spinal cord injury, and neurodegenerative disease [#27, #82].

The cargo of myeloid EVs is dynamically regulated by the activation state of the parent cell. EVs from pro-inflammatory microglia contain different miRNA profiles and protein composition compared to EVs from homeostatic or anti-inflammatory cells [#66]. These differences may contribute to the divergent effects of microglial activation states on surrounding cells. For example, miR-146a, which is enriched in EVs from anti-inflammatory microglia, can suppress inflammatory signaling in recipient cells by targeting components of the NF-kappaB pathway [#66]. The transfer of such regulatory miRNAs represents a mechanism by which myeloid cells can modulate the function of other cells over distance.

The use of EVs as therapeutic delivery vehicles has attracted considerable interest [#10, #82]. EVs can be loaded with drugs, nucleic acids, or proteins and can be engineered to target specific cell types through surface modification. Macrophage membrane-coated nanoparticles represent a related approach, in which synthetic nanoparticles are cloaked in macrophage membranes to evade immune recognition and target inflamed tissues [#100]. These biomimetic platforms have shown promise in preclinical models of various diseases, though their application to neurodegenerative disease is still in early stages.

## The Gut-Brain Axis and Systemic Influences on Myeloid Function

The gut microbiome has emerged as a significant modulator of neuroinflammation and neurodegeneration through the gut-brain axis [#1, #11, #89]. Gut bacteria produce metabolites, including short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate, that can influence immune function both locally and systemically [#15]. SCFAs are absorbed into the circulation and can cross the blood-brain barrier, where they may modulate microglial function. Germ-free mice, which lack a gut microbiome, exhibit altered microglial morphology and gene expression, and these changes can be partially reversed by colonization with specific bacterial species or by SCFA supplementation [#11, #89].

The composition of the gut microbiome changes with age and in neurodegenerative disease [#1, #62]. Patients with Alzheimer's disease and Parkinson's disease show alterations in gut microbial communities compared to healthy controls, though the specific changes reported vary between studies [#11, #89]. Whether these microbial changes contribute to disease pathogenesis or are consequences of disease-related factors such as diet, medication, or altered gut motility remains unclear. Studies in animal models have provided evidence for causal effects, as transplantation of fecal microbiota from Alzheimer's disease patients into germ-free mice can exacerbate pathology [#11].

The mechanisms by which gut microbes influence myeloid cell function in the brain are multiple. SCFAs can directly affect microglial function through activation of G protein-coupled receptors such as GPR43 and GPR109A, as well as through inhibition of histone deacetylases [#15]. These effects generally promote a more homeostatic or anti-inflammatory microglial phenotype. Gut microbes also influence the maturation and function of peripheral immune cells, including monocytes, which can then traffic to the brain [#1, #11]. The intestinal barrier integrity is compromised in some neurodegenerative conditions, allowing bacterial products such as lipopolysaccharide to enter the circulation and trigger systemic inflammation that can affect the brain [#28, #89].

The oral microbiome has also been implicated in neurodegenerative disease, particularly through the link between periodontal disease and Alzheimer's disease [#4]. Periodontal pathogens, including Porphyromonas gingivalis, can access the brain through various routes, including the bloodstream and peripheral nerves. These bacteria and their products can activate innate immune receptors in the brain, potentially contributing to neuroinflammation [#4, #55]. The systemic inflammation associated with periodontal disease may also affect myeloid cell function through circulating cytokines and other mediators.

The concept of the gut-liver-brain axis adds another layer of complexity, as liver-derived factors can influence both gut microbial composition and brain function [#103]. Bile acids, which are synthesized in the liver and modified by gut bacteria, signal through nuclear receptors such as FXR and TGR5 to regulate metabolism and inflammation [#45]. Dysregulation of bile acid metabolism has been reported in Alzheimer's disease and may influence myeloid cell function through systemic effects.

## Aging, Immunosenescence, and Myeloid Dysfunction

Aging is the strongest risk factor for most neurodegenerative diseases, and age-related changes in the immune system likely contribute to disease susceptibility [#5, #9, #16]. Immunosenescence refers to the progressive deterioration of immune function with age, characterized by reduced adaptive immune responses, increased susceptibility to infection, and chronic low-grade inflammation, termed inflammaging [#9, #16]. Myeloid cells are central to inflammaging, as aged macrophages and microglia exhibit altered cytokine secretion profiles and reduced phagocytic capacity.

The molecular mechanisms underlying age-related myeloid dysfunction are multiple. Cellular senescence, a state of irreversible cell cycle arrest accompanied by the secretion of pro-inflammatory factors (the senescence-associated secretory phenotype, SASP), accumulates in various tissues with age [#9, #67]. Senescent microglia have been identified in the aged brain, and their SASP may contribute to neuroinflammation and neurodegeneration. The accumulation of senescent cells is driven by various stressors, including oxidative damage, telomere shortening, and mitochondrial dysfunction [#29, #67]. Clearance of senescent cells using pharmacological agents, termed senolytics, has shown beneficial effects in mouse models of aging and neurodegeneration [#9, #67].

Mitochondrial dysfunction is a hallmark of aging and contributes to myeloid cell dysfunction through multiple mechanisms [#29, #86]. Aged microglia exhibit reduced mitochondrial respiratory capacity and increased reactive oxygen species production. Damaged mitochondria release mitochondrial DNA, which can activate the cGAS-STING pathway and promote inflammatory gene expression [#29, #81]. The accumulation of damaged mitochondria in aged myeloid cells reflects impaired mitophagy, and enhancing mitophagy has been proposed as a strategy to rejuvenate aged immune cells [#7, #29].

Epigenetic changes with age also influence myeloid cell function [#67, #91]. DNA methylation patterns change with age, and these changes can affect the expression of genes involved in inflammation and phagocytosis. Histone modifications and chromatin remodeling also contribute to age-related changes in myeloid cell gene expression. The potential reversibility of these epigenetic changes has motivated studies of epigenetic drugs, including histone deacetylase inhibitors, in models of aging and neurodegeneration [#91].

The interaction between aging and disease-specific factors is complex. While aging predisposes to neurodegeneration, not all aged individuals develop disease, suggesting that additional triggers are required. The concept of "inflammaging" proposes that chronic low-grade inflammation associated with aging creates a permissive environment for disease development [#9, #16]. In this view, age-related myeloid dysfunction may lower the threshold for pathological protein aggregation to trigger damaging neuroinflammation.

## Single-Cell Technologies and Myeloid Heterogeneity

The application of single-cell RNA sequencing and related technologies has transformed our understanding of myeloid cell heterogeneity in the brain [#8, #47, #70]. These approaches have revealed that microglia are not a uniform population but rather exist in multiple states that differ in gene expression, function, and spatial distribution. The identification of disease-associated microglia (DAM) in Alzheimer's disease models was a landmark finding, demonstrating that microglia can adopt specific states in response to pathology [#8].

The DAM phenotype is characterized by downregulation of homeostatic genes such as P2RY12 and CX3CR1 and upregulation of genes involved in phagocytosis, lipid metabolism, and lysosomal function, including TREM2, APOE, and LPL [#8, #47]. DAM cells are found in proximity to amyloid plaques and appear to represent an attempt to contain pathology. However, the relationship between DAM cells and disease progression is not simple. While some studies suggest that DAM cells are protective, others indicate that they may contribute to neurodegeneration through excessive inflammation or impaired function [#8, #47].

Single-cell analyses of human Alzheimer's disease brain tissue have identified microglial states that partially overlap with those found in mouse models but also exhibit species-specific features [#47, #98]. The APOE4 genotype is associated with alterations in microglial states, including increased abundance of lipid droplet-associated microglia [#47]. These findings highlight the importance of studying human tissue to validate and extend observations from animal models.

The spatial organization of myeloid cells in the diseased brain is increasingly recognized as important. Spatial transcriptomics and imaging approaches have revealed that microglial states are not randomly distributed but rather organized in relation to pathological features such as amyloid plaques [#8, #47]. This spatial organization likely reflects local cues from damaged neurons, aggregated proteins, and other glial cells. Understanding how microglial states are spatially regulated may inform strategies to modulate their function in specific brain regions.

The heterogeneity of infiltrating monocytes in neurodegenerative disease is less well characterized than that of microglia, partly due to the technical challenges of distinguishing these populations. However, recent studies using lineage tracing and single-cell approaches have begun to reveal the diversity of monocyte-derived cells in the diseased brain [#59, #98]. These cells may adopt states that resemble microglia or maintain distinct identities, and their functions may differ from those of resident microglia.

## Therapeutic Implications and Future Directions

The recognition that myeloid cells can exert protective functions in neurodegeneration has motivated therapeutic strategies aimed at enhancing these functions. Approaches under investigation include boosting phagocytic clearance of protein aggregates, promoting trophic factor secretion, modulating myeloid cell metabolism, and targeting specific signaling pathways that regulate myeloid cell phenotype [#8, #12, #48].

Enhancing microglial phagocytosis has been a major focus of therapeutic development. TREM2 agonism has been proposed as a strategy to enhance amyloid-beta clearance, though the development of TREM2 agonists has been challenging [#72]. Other approaches include targeting CD33, a sialic acid-binding receptor that inhibits microglial phagocytosis and is genetically associated with Alzheimer's disease risk [#8]. Blocking CD33 signaling has been shown to enhance amyloid-beta clearance in preclinical models. The modulation of complement receptors, which mediate opsonization-dependent phagocytosis, represents another potential approach [#42].

The repurposing of existing drugs to modulate myeloid cell function has also been explored. Non-steroidal anti-inflammatory drugs (NSAIDs) have been tested in Alzheimer's disease clinical trials, largely with negative results [#12]. However, these trials may have been confounded by the advanced disease stage of participants and the inability of some NSAIDs to adequately engage central targets. More selective approaches targeting specific inflammatory pathways, such as NLRP3 inhibitors or IL-1beta neutralizing antibodies, are in various stages of development [#24, #83].

Cell-based therapies using mesenchymal stem cells (MSCs) or their derivatives have shown promise in preclinical models of neurodegenerative disease [#13, #27]. MSCs exert immunomodulatory effects through paracrine mechanisms, including the secretion of anti-inflammatory cytokines and extracellular vesicles. The administration of MSCs or MSC-derived EVs has been shown to reduce neuroinflammation and improve functional outcomes in models of stroke, spinal cord injury, and Alzheimer's disease [#13, #27, #82]. However, the translation of these approaches to clinical practice faces challenges, including the optimal cell source, dosing, route of administration, and the durability of therapeutic effects.

The modulation of the gut microbiome represents an emerging therapeutic avenue [#11, #89]. Probiotics, prebiotics, and fecal microbiota transplantation have been tested in animal models of neurodegenerative disease with some beneficial effects. Dietary interventions that increase SCFA production, such as high-fiber diets, are also being explored [#15]. However, the clinical evidence for microbiome-based therapies in neurodegeneration remains limited, and the mechanisms by which gut microbes influence brain myeloid cells need further elucidation.

Several challenges confront the field. The heterogeneity of myeloid cell responses across disease stages and brain regions complicates the design of targeted therapies. A treatment that enhances microglial phagocytosis in early disease might be detrimental in later stages if it promotes excessive inflammation. The development of biomarkers to monitor myeloid cell states in living patients would facilitate patient stratification and treatment monitoring. The translation of findings from animal models to human disease remains challenging, as the immune systems of mice and humans differ in important respects [#70].

## Inconsistencies and Knowledge Gaps

Despite substantial progress, significant inconsistencies and knowledge gaps remain in our understanding of myeloid cell protective mechanisms in neurodegeneration. The extent to which findings from mouse models translate to human disease is uncertain. Many interventions that show benefit in mouse models have failed in human clinical trials, raising questions about the validity of these models [#12]. The genetic background of mouse strains, the timing and route of intervention, and the specific disease model used can all influence outcomes, making cross-study comparisons difficult.

The role of infiltrating monocytes in neurodegenerative disease remains particularly controversial. Some studies report substantial monocyte infiltration and contribution to pathology, while others find minimal infiltration under most conditions [#59]. These discrepancies may reflect technical differences in cell labeling and tracking methods, as well as genuine differences between disease models. The development of more reliable methods to distinguish resident microglia from infiltrating monocytes in human tissue would help resolve this issue.

The relationship between microglial activation states and disease outcomes is not straightforward. While the DAM phenotype is generally considered protective, some studies suggest that DAM cells may contribute to neurodegeneration through excessive inflammation or impaired function [#8, #47]. The temporal dynamics of microglial states are not well characterized, and it is unclear whether protective states can transition to detrimental states with disease progression. Longitudinal studies using in vivo imaging or serial sampling would be valuable.

The metabolic regulation of myeloid cell function in neurodegeneration is an area of active investigation, but many questions remain. The extent to which in vitro findings on macrophage polarization reflect in vivo microglial metabolism is uncertain [#113, #117]. The metabolic requirements for specific microglial functions, such as phagocytosis and trophic factor secretion, are not fully defined. The potential for metabolic interventions to modulate myeloid cell function in neurodegeneration has not been extensively explored.

The role of the gut microbiome in modulating myeloid cell function in the brain is supported by correlative evidence, but causal mechanisms are incompletely understood [#11, #89]. The specific microbial species and metabolites that influence brain myeloid cells need to be identified. The extent to which microbiome-targeted interventions can modify disease progression in humans remains to be established.

## Conclusion

Myeloid-derived monocytes and macrophages, particularly microglia, play complex and context-dependent roles in neurodegenerative diseases. Their protective functions include phagocytic clearance of pathological proteins, secretion of trophic factors, containment of damage, and regulation of inflammation. However, these same cells can adopt phenotypes that exacerbate neurodegeneration, particularly under conditions of chronic stimulation or age-related dysfunction. The challenge for therapeutic development lies in selectively enhancing protective functions while suppressing detrimental ones.

Recent advances in single-cell technologies have revealed remarkable heterogeneity in myeloid cell states, providing new opportunities for targeted intervention. The identification of specific microglial populations associated with protective or detrimental outcomes may enable more precise therapeutic approaches. The integration of genetic, environmental, and aging-related factors that influence myeloid cell function will be essential for developing personalized strategies.

The translation of preclinical findings to clinical benefit has been disappointing to date, highlighting the need for improved disease models and better biomarkers. The development of therapies that modulate myeloid cell function in neurodegeneration will require careful consideration of disease stage, patient genotype, and the balance between protective and detrimental immune responses. Despite these challenges, the potential to harness the reparative capacity of myeloid cells offers hope for new treatments for these devastating diseases.

# Structured Quality Scoring Table

| # | Study type | Framework | Instrument result | Design(0-3) | Methods/Validation(0-3) | Stats/Logic(0-3) | Total(0-9) | Grade |
|---|-----------|-----------|-------------------|-------------|--------------------------|--------------------|-------------|-------|
| 1 | Narrative review | NA | NA | 2 (comprehensive scope across microbiota types) | 2 (broad coverage but limited critical appraisal) | 2 (logical organization, some redundancy) | 6 | Medium |
| 2 | Narrative review | NA | NA | 2 (well-structured pathway overview) | 2 (extensive literature coverage, limited methodological detail) | 2 (clear mechanistic logic) | 6 | Medium |
| 3 | Narrative review | NA | NA | 2 (comprehensive NF-κB biology and therapy review) | 2 (broad synthesis, limited validation) | 2 (coherent translational framework) | 6 | Medium |
| 4 | Narrative review | NA | NA | 2 (integrative multi-system perspective) | 2 (expert synthesis, limited systematic methods) | 2 (strong mechanistic logic) | 6 | Medium |
| 5 | Narrative review | NA | NA | 2 (broad aging framework) | 2 (extensive but not systematic) | 2 (clear conceptual organization) | 6 | Medium |
| 6 | Narrative review | NA | NA | 2 (focused neuroinflammation scope) | 2 (good coverage, limited critical appraisal) | 2 (logical disease-by-disease structure) | 6 | Medium |
| 7 | Narrative review | NA | NA | 2 (comprehensive autophagy-disease overview) | 2 (strong mechanistic detail, limited methods) | 2 (coherent argumentation) | 6 | Medium |
| 8 | Narrative review | NA | NA | 2 (timely single-cell perspective) | 2 (good integration of recent data) | 2 (clear therapeutic rationale) | 6 | Medium |
| 9 | Narrative review | NA | NA | 2 (integrative aging-inflammation framework) | 2 (broad coverage, limited systematic approach) | 2 (logical signaling pathway organization) | 6 | Medium |
| 10 | Narrative review | NA | NA | 2 (comprehensive EV biology scope) | 2 (extensive coverage, limited critical analysis) | 2 (clear structure) | 6 | Medium |
| 11 | Narrative review | NA | NA | 2 (integrative gut-brain axis framework) | 2 (good mechanistic synthesis) | 2 (coherent therapeutic focus) | 6 | Medium |
| 12 | Narrative review | NA | NA | 2 (comprehensive AD overview) | 2 (broad clinical and mechanistic coverage) | 2 (clear translational logic) | 6 | Medium |
| 13 | Narrative review | NA | NA | 2 (broad stem cell therapy scope) | 2 (extensive but not systematic) | 2 (logical disease application structure) | 6 | Medium |
| 14 | Narrative review | NA | NA | 2 (focused nanotechnology-cancer scope) | 2 (good translational coverage) | 2 (clear clinical implementation logic) | 6 | Medium |
| 15 | Narrative review | NA | NA | 2 (focused SCFA-microbiome scope) | 2 (good mechanistic detail) | 2 (evolutionary-contextual logic) | 6 | Medium |
| 16 | Narrative review | NA | NA | 2 (comprehensive immunosenescence scope) | 2 (broad coverage, limited critical appraisal) | 2 (clear disease-linkage logic) | 6 | Medium |
| 17 | Narrative review | NA | NA | 2 (systematic heavy metal toxicity overview) | 2 (good toxicological detail) | 2 (clear exposure-outcome logic) | 6 | Medium |
| 18 | Narrative review | NA | NA | 2 (comprehensive stroke signaling review) | 2 (extensive pathway coverage) | 2 (clear therapeutic logic) | 6 | Medium |
| 19 | Narrative review | NA | NA | 2 (focused NLRP3 mechanism review) | 2 (good mechanistic depth) | 2 (clear regulatory framework) | 6 | Medium |
| 20 | Narrative review | NA | NA | 2 (broad ncRNA-disease scope) | 2 (expert synthesis, limited methods) | 2 (coherent therapeutic framework) | 6 | Medium |
| 21 | Narrative review | NA | NA | 2 (comprehensive sirtuin family review) | 2 (good mechanistic coverage) | 2 (clear structure) | 6 | Medium |
| 22 | Narrative review | NA | NA | 2 (focused curcumin anti-inflammatory scope) | 2 (good coverage of limitations) | 2 (clear countermeasure logic) | 6 | Medium |
| 23 | Narrative review | NA | NA | 2 (conceptual microglia semantics focus) | 2 (thoughtful conceptual analysis) | 2 (nuanced interpretive logic) | 6 | Medium |
| 24 | Narrative review | NA | NA | 2 (focused NLRP3 blocker therapeutics) | 2 (good drug development coverage) | 2 (clear translational logic) | 6 | Medium |
| 25 | Narrative review | NA | NA | 2 (comprehensive NP toxicity scope) | 2 (good mechanistic and model coverage) | 2 (clear risk assessment logic) | 6 | Medium |
| 26 | Narrative review | NA | NA | 2 (comprehensive SCI review) | 2 (broad mechanistic and therapeutic coverage) | 2 (clear repair strategy logic) | 6 | Medium |
| 27 | Narrative review | NA | NA | 2 (focused MSC secretion profile) | 2 (good paracrine mechanism coverage) | 2 (clear therapeutic application logic) | 6 | Medium |
| 28 | Narrative review | NA | NA | 2 (focused BBB-inflammation scope) | 2 (good mechanistic detail) | 2 (clear protective signaling logic) | 6 | Medium |
| 29 | Narrative review | NA | NA | 2 (integrative mitochondria-aging framework) | 2 (broad mechanistic coverage) | 2 (clear therapeutic advance logic) | 6 | Medium |
| 30 | Narrative review | NA | NA | 2 (focused pyroptosis-cancer scope) | 2 (good mechanistic integration) | 2 (clear dual-role logic) | 6 | Medium |
| 31 | Narrative review | NA | NA | 2 (comprehensive JAK-STAT review) | 2 (good pathway and disease coverage) | 2 (clear therapeutic logic) | 6 | Medium |
| 32 | Narrative review | NA | NA | 2 (integrative iron-ferroptosis framework) | 2 (good mechanistic depth) | 2 (clear therapeutic prospects logic) | 6 | Medium |
| 33 | Original research | NA | NA | 3 (single-cell multi-omics design) | 3 (rigorous snRNA-seq methodology) | 3 (strong statistical validation) | 9 | High |
| 34 | Narrative review | NA | NA | 2 (comprehensive macrophage biology scope) | 2 (expert synthesis, limited systematic methods) | 2 (clear developmental choreography logic) | 6 | Medium |
| 35 | Narrative review | NA | NA | 2 (focused chemokine pair review) | 2 (good molecular and functional detail) | 2 (clear pharmacological intervention logic) | 6 | Medium |
| 36 | Narrative review | NA | NA | 2 (broad free radical-antioxidant scope) | 2 (good basic science coverage) | 2 (clear health impact logic) | 6 | Medium |
| 37 | Narrative review | NA | NA | 2 (focused GPX4 multi-function review) | 2 (good mechanistic depth) | 2 (clear disease relevance logic) | 6 | Medium |
| 38 | Narrative review | NA | NA | 2 (comprehensive hyperuricemia scope) | 2 (good mechanistic and therapeutic coverage) | 2 (clear disease spectrum logic) | 6 | Medium |
| 39 | Narrative review | NA | NA | 2 (focused ferroptosis therapeutics) | 2 (good drug development coverage) | 2 (clear novel target logic) | 6 | Medium |
| 40 | Narrative review | NA | NA | 2 (focused BDNF-AD scope) | 2 (good synaptic mechanism coverage) | 2 (clear pharmaceutical potential logic) | 6 | Medium |
| 41 | Narrative review | NA | NA | 2 (focused sleep-immunity scope) | 2 (good epidemiological and mechanistic integration) | 2 (clear risk-outcome logic) | 6 | Medium |
| 42 | Narrative review | NA | NA | 2 (focused glial-AD neuroinflammation) | 2 (good cell-type specific coverage) | 2 (clear modulator logic) | 6 | Medium |
| 43 | Narrative review | NA | NA | 2 (focused DC migration scope) | 2 (good mechanistic detail) | 2 (clear immunity logic) | 6 | Medium |
| 44 | Narrative review | NA | NA | 2 (conceptual meta-hallmarks framework) | 2 (thoughtful integrative synthesis) | 2 (clear aging-cancer convergence logic) | 6 | Medium |
| 45 | Narrative review | NA | NA | 2 (comprehensive bile acid scope) | 2 (good metabolic signaling coverage) | 2 (clear therapeutic target logic) | 6 | Medium |
| 46 | Narrative review | NA | NA | 2 (comprehensive cholesterol homeostasis scope) | 2 (good disease-specific coverage) | 2 (clear targeted therapeutics logic) | 6 | Medium |
| 47 | Original research | NA | NA | 3 (single-nucleus RNA-seq discovery design) | 3 (rigorous lipid droplet characterization) | 3 (strong multi-omics validation) | 9 | High |
| 48 | Narrative review | NA | NA | 2 (focused AD neuroinflammation scope) | 2 (expert synthesis, limited systematic methods) | 2 (clear disease mechanism logic) | 6 | Medium |
| 49 | Narrative review | NA | NA | 2 (focused macrophage metabolism scope) | 2 (good immunometabolism coverage) | 2 (clear homeostasis-pathology logic) | 6 | Medium |
| 50 | Narrative review | NA | NA | 2 (comprehensive acylcarnitine scope) | 2 (good biomarker and therapeutic coverage) | 2 (clear clinical translation logic) | 6 | Medium |
| 51 | Narrative review | NA | NA | 2 (comprehensive TRP channel review) | 2 (good structural-functional coverage) | 2 (clear therapeutic intervention logic) | 6 | Medium |
| 52 | Narrative review | NA | NA | 2 (focused stroke neuroinflammation) | 2 (good acute/subacute coverage) | 2 (clear ischemic-hemorrhagic logic) | 6 | Medium |
| 53 | Narrative review | NA | NA | 2 (comprehensive hypoxia signaling scope) | 2 (good mechanistic and therapeutic coverage) | 2 (clear disease implication logic) | 6 | Medium |
| 54 | Narrative review | NA | NA | 2 (broad nanotechnology-inflammation scope) | 2 (good prevention-treatment coverage) | 2 (clear application logic) | 6 | Medium |
| 55 | Narrative review | NA | NA | 2 (focused oral microbiome scope) | 2 (good ecological framework) | 2 (clear dysbiosis-host logic) | 6 | Medium |
| 56 | Narrative review | NA | NA | 2 (comprehensive OSAS scope) | 2 (good pathophysiological coverage) | 2 (clear therapeutic approach logic) | 6 | Medium |
| 57 | Narrative review | NA | NA | 2 (comprehensive inflammasome 360° view) | 2 (expert synthesis, broad coverage) | 2 (clear activation-death-disease logic) | 6 | Medium |
| 58 | Narrative review (RETRACTED) | NA | NA | 1 (retracted publication) | 1 (validity compromised) | 1 (conclusions unreliable) | 3 | Low |
| 59 | Narrative review | NA | NA | 2 (focused peripheral-central crosstalk) | 2 (good research prospectus framework) | 2 (clear crosstalk logic) | 6 | Medium |
| 60 | Narrative review | NA | NA | 2 (comprehensive astrocyte-CNS scope) | 2 (good disease-specific coverage) | 2 (clear therapeutic frontier logic) | 6 | Medium |
| 61 | Narrative review | NA | NA | 2 (focused NF-κB inflammation-cancer) | 2 (good mechanistic integration) | 2 (clear dual-role logic) | 6 | Medium |
| 62 | Narrative review | NA | NA | 2 (focused aging microbiome-immunity) | 2 (good age-related coverage) | 2 (clear host immunity logic) | 6 | Medium |
| 63 | Systematic review | AMSTAR-2 | Low confidence | 2 (systematic search but limited protocol detail) | 2 (defined inclusion criteria, limited quality assessment) | 2 (clear synthesis of reactive astrocyte roles) | 6 | Medium |
| 64 | Narrative review | NA | NA | 2 (comprehensive PTM scope) | 2 (good mechanistic breadth) | 2 (clear therapeutic implication logic) | 6 | Medium |
| 65 | Narrative review | NA | NA | 2 (focused mitochondrial transfer scope) | 2 (good emerging concept coverage) | 2 (clear revitalization logic) | 6 | Medium |
| 66 | Narrative review | NA | NA | 2 (focused exosomal ncRNA scope) | 2 (good mechanistic coverage) | 2 (clear disease relevance logic) | 6 | Medium |
| 67 | Narrative review | NA | NA | 2 (integrative senescence-aging framework) | 2 (good convergence coverage) | 2 (clear regulation-intervention logic) | 6 | Medium |
| 68 | Narrative review | NA | NA | 2 (focused atherosclerosis inflammation) | 2 (good pathophysiological detail) | 2 (clear mechanism-disease logic) | 6 | Medium |
| 69 | Narrative review | NA | NA | 2 (focused stem cell aging scope) | 2 (expert synthesis, limited methods) | 2 (clear rejuvenation logic) | 6 | Medium |
| 70 | Narrative review | NA | NA | 2 (focused immune aging single-cell scope) | 2 (good technological emphasis) | 2 (clear resolution-based logic) | 6 | Medium |
| 71 | Narrative review | NA | NA | 2 (comprehensive cell communication scope) | 2 (good emerging concept coverage) | 2 (clear clinical implication logic) | 6 | Medium |
| 72 | Narrative review | NA | NA | 2 (focused TREM receptor biology) | 2 (good receptor family coverage) | 2 (clear immune function logic) | 6 | Medium |
| 73 | Narrative review | NA | NA | 2 (focused pyroptosis tissue damage) | 2 (good inflammatory mechanism coverage) | 2 (clear damage logic) | 6 | Medium |
| 74 | Narrative review | NA | NA | 2 (focused plant EV scope) | 2 (good comparative coverage) | 2 (clear biomedical application logic) | 6 | Medium |
| 75 | Consensus report | NA | NA | 2 (expert consensus framework) | 2 (NCCD collaborative methodology) | 2 (clear cell death classification logic) | 6 | Medium |
| 76 | Narrative review | NA | NA | 2 (comprehensive AD pathology scope) | 2 (good molecular mechanism coverage) | 2 (clear therapy logic) | 6 | Medium |
| 77 | Narrative review | NA | NA | 2 (comprehensive zinc metabolism scope) | 2 (good cellular signaling coverage) | 2 (clear disease-target logic) | 6 | Medium |
| 78 | Narrative review | NA | NA | 2 (comprehensive lysosome scope) | 2 (good multi-function coverage) | 2 (clear therapy logic) | 6 | Medium |
| 79 | Narrative review | NA | NA | 2 (focused depression immune targets) | 2 (good precision medicine framework) | 2 (clear therapeutic development logic) | 6 | Medium |
| 80 | Narrative review | NA | NA | 2 (comprehensive immune metabolism scope) | 2 (good pathway coverage) | 2 (clear intervention logic) | 6 | Medium |
| 81 | Narrative review | NA | NA | 2 (focused cGAS-STING scope) | 2 (expert synthesis, limited methods) | 2 (clear DNA-sensing logic) | 6 | Medium |
| 82 | Narrative review | NA | NA | 2 (focused exosome engineering scope) | 2 (good therapeutic platform coverage) | 2 (clear drug delivery logic) | 6 | Medium |
| 83 | Narrative review | NA | NA | 2 (focused NLRP3 drugging scope) | 2 (expert drug development coverage) | 2 (clear signaling-target logic) | 6 | Medium |
| 84 | Narrative review | NA | NA | 2 (focused ribosome biogenesis scope) | 2 (good emerging disease coverage) | 2 (clear therapeutic target logic) | 6 | Medium |
| 85 | Narrative review | NA | NA | 2 (focused long COVID mechanisms) | 2 (good mechanistic synthesis) | 2 (clear therapeutic path logic) | 6 | Medium |
| 86 | Narrative review | NA | NA | 2 (focused mitochondria-cell death scope) | 2 (good programmed death coverage) | 2 (clear age-related target logic) | 6 | Medium |
| 87 | Narrative review | NA | NA | 2 (integrative neurodegeneration framework) | 2 (good common mechanism synthesis) | 2 (clear treatment strategy logic) | 6 | Medium |
| 88 | Narrative review | NA | NA | 2 (focused pyroptosis-immunity scope) | 2 (good anticancer immunity coverage) | 2 (clear therapeutic logic) | 6 | Medium |
| 89 | Narrative review | NA | NA | 2 (focused microbiota-AD scope) | 2 (good neuroinflammation-synapse coverage) | 2 (clear gut-brain logic) | 6 | Medium |
| 90 | Narrative review | NA | NA | 2 (focused exercise metabolism scope) | 2 (expert synthesis, limited methods) | 2 (clear adaptation logic) | 6 | Medium |
| 91 | Narrative review | NA | NA | 2 (comprehensive epigenetics drug scope) | 2 (good paradigm coverage) | 2 (clear challenge-future logic) | 6 | Medium |
| 92 | Narrative review | NA | NA | 2 (comprehensive pyroptosis scope) | 2 (good regulation-clinical coverage) | 2 (clear health-disease logic) | 6 | Medium |
| 93 | Narrative review | NA | NA | 2 (focused GBM microenvironment scope) | 2 (good tumor immunity coverage) | 2 (clear emerging concept logic) | 6 | Medium |
| 94 | Narrative review | NA | NA | 2 (focused galectin immunity scope) | 2 (expert synthesis, limited methods) | 2 (clear infection logic) | 6 | Medium |
| 95 | Narrative review | NA | NA | 2 (integrative dopamine-immunity scope) | 2 (good neurotransmitter-immune coverage) | 2 (clear disease logic) | 6 | Medium |
| 96 | Narrative review | NA | NA | 2 (focused BET family scope) | 2 (good epigenetic-immune coverage) | 2 (clear disease logic) | 6 | Medium |
| 97 | Narrative review | NA | NA | 2 (focused neurogenesis-depression scope) | 2 (good neuroimmune coverage) | 2 (clear hippocampal logic) | 6 | Medium |
| 98 | Narrative review | NA | NA | 2 (focused neuroimmune AD axis) | 2 (good genetic-immune integration) | 2 (clear multi-system logic) | 6 | Medium |
| 99 | Narrative review | NA | NA | 2 (integrative periphery-brain PD scope) | 2 (good innate-adaptive coverage) | 2 (clear alpha-synuclein logic) | 6 | Medium |
| 100 | Narrative review | NA | NA | 2 (focused macrophage membrane NP scope) | 2 (good biomimetic platform coverage) | 2 (clear targeted delivery logic) | 6 | Medium |
| 101 | Narrative review | NA | NA | 2 (comprehensive AA metabolism scope) | 2 (good eicosanoid pathway coverage) | 2 (clear health-disease logic) | 6 | Medium |
| 102 | Narrative review | NA | NA | 2 (focused nutrition-immunity scope) | 2 (good micronutrient coverage) | 2 (clear nutritional support logic) | 6 | Medium |
| 103 | Narrative review | NA | NA | 2 (integrative gut-liver-brain scope) | 2 (good three-way axis coverage) | 2 (clear therapeutic intervention logic) | 6 | Medium |
| 104 | Narrative review | NA | NA | 2 (focused TLR-PD scope) | 2 (good neuroinflammation coverage) | 2 (clear receptor-disease logic) | 6 | Medium |
| 105 | Narrative review | NA | NA | 2 (focused vimentin scope) | 2 (good cytoskeletal function coverage) | 2 (clear disease relevance logic) | 6 | Medium |
| 106 | Narrative review | NA | NA | 2 (focused protein modification-metabolic scope) | 2 (good PTM-disease coverage) | 2 (clear targeted therapy logic) | 6 | Medium |
| 107 | Narrative review | NA | NA | 2 (comprehensive PRR scope) | 2 (good innate-adaptive bridge coverage) | 2 (clear therapeutic potential logic) | 6 | Medium |
| 108 | Narrative review | NA | NA | 2 (focused amyloid plaque components) | 2 (good extracellular protein coverage) | 2 (clear AD pathology logic) | 6 | Medium |
| 109 | Narrative review | NA | NA | 2 (comprehensive ferroptosis scope) | 2 (good molecular network coverage) | 2 (clear health-disease significance logic) | 6 | Medium |
| 110 | Systematic review | AMSTAR-2 | Low confidence | 2 (systematic search, limited protocol detail) | 2 (defined inclusion, limited quality assessment) | 2 (clear skin application synthesis) | 6 | Medium |
| 111 | Narrative review | NA | NA | 2 (focused complosome scope) | 2 (good intracellular complement coverage) | 2 (clear novel concept logic) | 6 | Medium |
| 112 | Narrative review | NA | NA | 2 (focused nanomaterial immunotherapy) | 2 (good strategy coverage) | 2 (clear challenge-opportunity logic) | 6 | Medium |
| 113 | Narrative review | NA | NA | 2 (focused amino acid-macrophage scope) | 2 (good metabolic pathway coverage) | 2 (clear polarization logic) | 6 | Medium |
| 114 | Narrative review | NA | NA | 2 (comprehensive TFEB scope) | 2 (good regulatory mechanism coverage) | 2 (clear disease association logic) | 6 | Medium |
| 115 | Narrative review | NA | NA | 2 (focused IDO1 scope) | 2 (good enzymatic mechanism coverage) | 2 (clear immunoregulatory logic) | 6 | Medium |
| 116 | Narrative review | NA | NA | 2 (focused brain border immunity) | 2 (expert synthesis, limited methods) | 2 (clear neuroimmunology logic) | 6 | Medium |
| 117 | Narrative review | NA | NA | 2 (focused microglia metabolism scope) | 2 (good metabolic reprogramming coverage) | 2 (clear phenotype-function logic) | 6 | Medium |
| 118 | Narrative review | NA | NA | 2 (comprehensive inflammasome scope) | 2 (good therapeutic target coverage) | 2 (clear disease logic) | 6 | Medium |
| 119 | Narrative review | NA | NA | 2 (focused SCI microenvironment scope) | 2 (good translational research coverage) | 2 (clear imbalance logic) | 6 | Medium |
| 120 | Narrative review | NA | NA | 2 (focused cuprizone model scope) | 2 (good demyelination mechanism coverage) | 2 (clear intrinsic-extrinsic logic) | 6 | Medium |

**Note on scoring rationale:** The vast majority of these papers are high-quality narrative reviews published in Tier 1 journals. They consistently score 2/3 across dimensions due to: (1) comprehensive but non-systematic designs typical of narrative reviews; (2) extensive literature coverage without formal validation methods; (3) coherent mechanistic logic without quantitative statistical analysis. The two original research papers (#33, #47) score higher due to rigorous experimental designs and statistical validation. The retracted paper (#58) is appropriately downgraded. The two systematic reviews (#63, #110) receive AMSTAR-2 low confidence ratings due to limited protocol transparency and quality assessment documentation.


## 🔎 引用核验报告（生成后自动回查）

共回查引用 67 条：通过 67 条，未通过/待人工核验 0 条。


| 引用 | 状态 |
|---|---|

| `[#1]` | ✅ 检索集内（Microbiota in health and diseases） |
| `[#2]` | ✅ 检索集内（PI3K/AKT/mTOR signaling transduction） |
| `[#4]` | ✅ 检索集内（Local and systemic mechanisms linkin） |
| `[#5]` | ✅ 检索集内（Aging and aging-related diseases: fr） |
| `[#6]` | ✅ 检索集内（Role of neuroinflammation in neurode） |
| `[#7]` | ✅ 检索集内（Autophagy in major human diseases） |
| `[#8]` | ✅ 检索集内（Microglia in neurodegenerative disea） |
| `[#9]` | ✅ 检索集内（Inflammation and aging: signaling pa） |
| `[#10]` | ✅ 检索集内（Extracellular vesicles as tools and ） |
| `[#11]` | ✅ 检索集内（Microbiota–gut–brain axis and its th） |
| `[#12]` | ✅ 检索集内（Recent advances in Alzheimer’s disea） |
| `[#13]` | ✅ 检索集内（Stem cell-based therapy for human di） |
| `[#15]` | ✅ 检索集内（Microbial Regulation of Host Physiol） |
| `[#16]` | ✅ 检索集内（Immunosenescence: molecular mechanis） |
| `[#18]` | ✅ 检索集内（Signaling pathways involved in ische） |
| `[#19]` | ✅ 检索集内（An update on the regulatory mechanis） |
| `[#23]` | ✅ 检索集内（The semantics of microglia activatio） |
| `[#24]` | ✅ 检索集内（NLRP3 and pyroptosis blockers for tr） |
| `[#27]` | ✅ 检索集内（The secretion profile of mesenchymal） |
| `[#28]` | ✅ 检索集内（The blood–brain barrier in systemic ） |
| `[#29]` | ✅ 检索集内（Mitochondria in oxidative stress, in） |
| `[#30]` | ✅ 检索集内（Role of pyroptosis in inflammation a） |
| `[#34]` | ✅ 检索集内（Tissue-specific macrophages: how the） |
| `[#35]` | ✅ 检索集内（The chemokines CXCL8 and CXCL12: mol） |
| `[#40]` | ✅ 检索集内（Brain-derived neurotrophic factor in） |
| `[#42]` | ✅ 检索集内（Astrocytic and microglial cells as t） |
| `[#45]` | ✅ 检索集内（Bile acid metabolism and signaling i） |
| `[#47]` | ✅ 检索集内（APOE4/4 is linked to damaging lipid ） |
| `[#48]` | ✅ 检索集内（Neuroinflammation in Alzheimer disea） |
| `[#49]` | ✅ 检索集内（Metabolism of tissue macrophages in ） |
| `[#52]` | ✅ 检索集内（Neuroinflammation in Acute Ischemic ） |
| `[#53]` | ✅ 检索集内（Hypoxia signaling in human health an） |
| `[#55]` | ✅ 检索集内（The oralome and its dysbiosis: New i） |
| `[#57]` | ✅ 检索集内（A 360° view of the inflammasome: Mec） |
| `[#59]` | ✅ 检索集内（Peripheral and central immune system） |
| `[#60]` | ✅ 检索集内（Astrocytes in human central nervous ） |
| `[#62]` | ✅ 检索集内（The aging gut microbiome and its imp） |
| `[#63]` | ✅ 检索集内（Roles of neuropathology-associated r） |
| `[#65]` | ✅ 检索集内（Intercellular mitochondrial transfer） |
| `[#66]` | ✅ 检索集内（Roles and mechanisms of exosomal non） |
| `[#67]` | ✅ 检索集内（Inflammation, epigenetics, and metab） |
| `[#70]` | ✅ 检索集内（Immune ageing at single-cell resolut） |
| `[#72]` | ✅ 检索集内（The biology of TREM receptors） |
| `[#73]` | ✅ 检索集内（Pyroptosis-induced inflammation and ） |
| `[#75]` | ✅ 检索集内（Apoptotic cell death in disease—Curr） |
| `[#78]` | ✅ 检索集内（Role of lysosomes in physiological a） |
| `[#80]` | ✅ 检索集内（Metabolic regulation of the immune s） |
| `[#81]` | ✅ 检索集内（New frontiers in the cGAS-STING intr） |
| `[#82]` | ✅ 检索集内（Exosome engineering in cell therapy ） |
| `[#83]` | ✅ 检索集内（Drugging the NLRP3 inflammasome: fro） |
| `[#86]` | ✅ 检索集内（Mitochondria-associated programmed c） |
| `[#89]` | ✅ 检索集内（Microbiota in neuroinflammation and ） |
| `[#91]` | ✅ 检索集内（Epigenetics-targeted drugs: current ） |
| `[#92]` | ✅ 检索集内（Pyroptosis in health and disease: me） |
| `[#98]` | ✅ 检索集内（The neuroimmune axis of Alzheimer’s ） |
| `[#99]` | ✅ 检索集内（Periphery and brain, innate and adap） |
| `[#100]` | ✅ 检索集内（Macrophage cell membrane-based nanop） |
| `[#103]` | ✅ 检索集内（Gut liver brain axis in diseases: th） |
| `[#104]` | ✅ 检索集内（The role of Toll-like receptors and ） |
| `[#107]` | ✅ 检索集内（Pattern recognition receptors: funct） |
| `[#108]` | ✅ 检索集内（Extracellular protein components of ） |
| `[#113]` | ✅ 检索集内（More than just protein building bloc） |
| `[#115]` | ✅ 检索集内（Indoleamine 2,3‐dioxygenase 1 (IDO1)） |
| `[#116]` | ✅ 检索集内（Brain borders at the central stage o） |
| `[#117]` | ✅ 检索集内（Microglia reprogram metabolic profil） |
| `[#118]` | ✅ 检索集内（The role of inflammasomes in human d） |
| `[#120]` | ✅ 检索集内（Oligodendrocyte death and myelin los） |


### 引用内容一致性抽查（AI辅助）
[4]: 存疑 - 正文未直接引用[4]对应内容，且该摘要为空，无法核实一致性。
[6]: 一致 - 正文称神经退行性疾病共享蛋白错误折叠等特征，摘要支持炎症在神经退行性疾病中的关键作用，但正文未明确引用[6]的具体内容，需结合上下文判断。
[8]: 存疑 - 正文未直接引用[8]对应内容，摘要提及小胶质细胞异质性，但正文摘录中无对应表述。
[10]: 存疑 - 正文未直接引用[10]对应内容，摘要关于细胞外囊泡的描述与正文主题相关，但无具体引用对应。

整体不一致 - 正文摘录中未明确展示[4]、[6]、[8]、[10]的引用位置，无法逐条核实一致性，且[4]无摘要，故无法判定整体一致。

---

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### 导出的参考文献文件
- `/root/Downloads/智阅/refs_20260907_154538.ris`
- `/root/Downloads/智阅/refs_20260907_154538.bib`
- `/root/Downloads/智阅/refs_20260907_154538_pmids.txt`
- `/root/Downloads/智阅/refs_20260907_154538_endnote.xml`

### 综述导出文件
- Markdown: `/root/Downloads/智阅/综述_20260907_154538.md`
- Word: `/root/Downloads/智阅/综述_20260907_154538_Word.docx`