Abstract
The etiology of various neurodegenerative disorders that mainly affect the central nervous system including (but not limited to) Alzheimer’s disease, Parkinson’s disease and Huntington’s disease has classically been attributed to neuronal defects that culminate with the loss of specific neuronal populations. However, accumulating evidence suggests that numerous immune effector cells and the products thereof (including cytokines and other soluble mediators) have a major impact on the pathogenesis and/or severity of these and other neurodegenerative syndromes. These observations not only add to our understanding of neurodegenerative conditions but also imply that (at least in some cases) therapeutic strategies targeting immune cells or their products may mediate clinically relevant neuroprotective effects. Here, we critically discuss immunological mechanisms of central neurodegeneration and propose potential strategies to correct neurodegeneration-associated immunological dysfunction with therapeutic purposes.
Similar content being viewed by others
Introduction
Neurodegenerative disorders (NDs) are a heterogeneous group of pathologies that is characterized by the progressive degeneration of the structure and function of the central or peripheral nervous system1,2,3. Severity and propensity to progression not only vary across different NDs, but also across patients presenting with the same pathology, which considerably complicates the effectiveness of therapeutic interventions4. In fact, no disease-modifying therapeutic strategies are currently available for most NDs5,6,7, perhaps with the exception of lecanemab, a controversial agent recently licensed by the US Food and Drug Administration (FDA) for the therapy of early Alzheimer’s disease (AD)8.
Common NDs affecting the central nervous system (CNS) including but not limited to AD, Parkinson’s disease (PD), and Huntington’s disease (HD) are generally attributed to intracellular defects in specific neuronal populations that over time compromise cellular homeostasis (often along with the progressive accumulation of specific proteins within neurons or in their microenvironment), ultimately culminating with widespread or localized neuronal loss coupled with clinical cognitive, behavioral or motor symptoms1,3,9. In line with this notion, while juvenile variants of central NDs exist10, the prevalence and severity of most NDs increases with age11. Moreover, a number of genetic mutations affecting intracellular processes have been associated with an increased risk for central NDs12,13. For instance, mutations in amyloid beta precursor protein (APP), which encodes the precursor of the AD pathognomonic amyloid beta (Aβ) peptide, is associated with an increased risk for AD1. Similarly, most cases of HD are associated with mutations in huntingtin (HTT), which results in the generation of an altered HTT variant with pathogenic features9. That said, some NDs are not necessarily associated with genetic predisposition14,15, suggesting that additional factors may be involved in their pathogenesis.
A number of non-genetic factors have been proposed as contributors to the pathogenesis of NDs, including (but not limited to): (1) the abundance and composition of the gut microbiome16,17, (2) a history of infection with viral or bacterial pathogens18, (3) the existence of subjacent or overt cardiovascular and metabolic disorders19, as well as (4) dysfunctions of the innate or adaptive immune system20,21 (Box 1). Recent data from other biomedical disciplines point indeed to an underappreciated contribution of dysregulated immunity to the pathogenesis of disorders that have classically been attributed to cell-intrinsic mechanisms, including various cardiovascular conditions22,23 and cancer24. Moreover, microglial cells, which play a major role in the development of multiple NDs (see below), are brain-resident cells of hematopoietic origin with macrophage-like functions, which render them preferential interactors of other potentially pathogenic immune cells25.
Here, we discuss immunological mechanisms that promote central neurodegeneration in the context of human NDs and propose potential strategies to correct neurodegeneration-associated immunological dysfunctions with therapeutic purposes. Conversely, immunological aspects of peripheric NDs including multiple sclerosis and amyotrophic lateral sclerosis have been extensively covered elsewhere26,27, and hence will not be covered in this review.
Alzheimer’s disease
AD, which is the most common cause of dementia amongst the elderly, is characterized by a progressive loss of cognitive functions and memory associated with the accumulation of extracellular Aβ plaques and intracellular microtubule associated protein tau (MAPT, best known as tau) neurofibrillary tangles1.
AD has been consistently linked to genetic alterations in apolipoprotein E (APOE), encoding a protein involved in lipid metabolism28, as well as in a number of genes involved in innate immunity and microglia activation, notably triggering receptor expressed on myeloid cells 2 (TREM2), encoding a plasma membrane receptor that promotes phagocytosis29,30,31; complement C3b/C4b receptor 1 (CR1), encoding a complement component32; CD3333,34; major histocompatibility complex, class II, DR beta 1 (HLA-DRB1), HLA-DRB5 and HLA-DR15, all encoding MHC molecules35,36; protein tyrosine kinase 2 beta (PTK2B), inositol polyphosphate-5-phosphatase D (INPP5D), and phospholipase C gamma 2 (PLCG2), all encoding intracellular signal transducers31,35; and ABI family member 3 (ABI3), encoding an adaptor protein31, pointing to microglia-driven neuroinflammation as a major pathogenic determinant of this ND.
Abundant preclinical data suggest that microglial activation may have a context- and disease stage-dependent effect on the progression of AD. On the one hand, inhibition of TREM2 by genetic or pharmacological strategies has been associated with limited microglial activity and neuroprotection in various mouse models of AD and tau pathology, including mice expressing five protein variants associated with familial AD (i.e., 5XFAD mice)37,38,39, mice expressing a human pathogenic variant of tau (so-called P301S mice)40,41, P301S mice expressing human AD-linked variant of APOE (i.e., APOE4)42, as well as 5XFAD mice intracerebrally administered with sarkosyl-insoluble tau aggregates isolated from the frontal cortex of human AD brain tissue43,44,45. However, TREM2 overexpression as well as increased TREM2 activation upon inhibition of membrane shedding have also been linked with improved biochemical and cognitive manifestations of AD in rodent models of the disease46,47. Thus, TREM2 appears to influence AD progression in a complex manner that may involve an initial beneficial impact related to the degradation of amyloid plaques and a subsequent detrimental impact linked to neuroinflammation.
To add yet another layer of complexity, in at least some AD models, while Trem2 haploinsufficiency appears to aggravate tau pathology in mice, complete Trem2 loss reportedly limits tau-driven microglial activation and atrophy48. Whether these apparently contradictory findings may relate to the differential activation of inflammatory responses in cells other than the microglia, such as oligodendrocytes49, remains to be further investigated. The existence of different microglial clusters as documented by modern single-cell sequencing technologies may also explain, at least in part, the apparently context-dependent impact of TREM2 on AD progression in mice. For instance, a novel type of neurodegenerative disease-associated microglia (DAM) has been shown to mediate neuroprotective effects in 5XFAD mice via a mechanism that at least initially involves TREM2 signalling50. Similar results have been obtained in mice expressing pathogenic APP variants (namely, AppNL-G-F mice), a scenario in which APOE expression by a DAM-like microglia was positively associated with an improved clearance of Aβ plaques51. In line with this notion, APOE has been shown to promote AD progression in mice bearing pathogenic APP and presenilin 1 (PSEN1, best known as PS1) variants (namely, APP-PS1 mice)52 and P301S mice53, a neurodegenerative mechanism mapping to the subset of microglia that exhibit a common disease-associated phenotype in mice and humans52,54.
Importantly, at least part of these APOE-associated mechanisms leading to neurodegeneration have been mapped to the inability of AD-linked APOE variants to preserve homeostatic (tolerogenic) microglial functions, culminating with the expression of multiple pro-inflammatory transcription factors52. In line with this possibility, APOE expression in astrocytes favors the polarization of microglia towards a DAM state in P301S mice54. Moreover, neuronal expression of APOE4 drives a specific DAM subset with potent neurodegenerative effects in an APOE4-expressing tauopathy mouse model, an effect that can be circumvented via neuron-specific ApoE deletion55. That said, human AD-associated microglia (HAM) as characterized by RNA sequencing from frozen samples of frontal cortex from AD-affected individuals appears to exhibit little transcriptional resemblance with the DAM as identified in mouse AD models56, with the notable exception of a common APOE overexpression57. Moreover, the HAM signature appears to be detectable also in patients with non-AD NDs, which is not the case for the DAM transcriptional profile56.
Thus, while initial microglial engagement has beneficial effects on AD progression at least partly emerging from the clearance of Aβ deposits, the overactivation of microglia has consistently been attributed a neurotoxic activity related to accrued oxidative stress and inflammation. Interestingly, such overactivation has been reported to culminate with microglial dystrophy58,59,60, a phenotype that appears to be common to multiple NDs beyond AD61,62,63. Additional work is required to identify strategies to finely modulate microglial functions for the treatment of AD.
Importantly, pro-inflammatory molecules secreted by the activated microglia including interleukin 1A (IL1A), tumor necrosis factor (TNF) and complement C1q A chain (C1QA) have been shown to promote astrocyte activation, resulting not only in a loss of phagocytic and synapse-promoting activity, but also in the secretion of neurotoxins that promotes neuronal and oligodendrocyte death64. In line with a pathogenic role for astrocytes in AD, astrocytic tau accumulation in the dentate gyrus has been shown to promote neuronal dysfunction and memory deficits in mice65. Moreover, reactive astrocytes have been identified in early stages of human AD and appear to be present ubiquitously throughout disease progression66. Moreover, while mildly reactive astrocytes have limited neurotoxic potential, severe astrocyte activation has been linked to neurotoxic and ultimately pathogenic hydrogen peroxide production via monoamine oxidase B (MAOB), at least in mice67. That said, astrocytes resemble microglia in being highly heterogenous and exhibiting an age-dependent decline in neuroprotective activity68,69. In line with this notion, a disease-associated astrocyte (DAA) transcriptional profile as identified in multiple rodent models of AD appears to emerge early during disease progression and exacerbate over time, a pathogenic progression also observed in aged wild-type mice and humans70.
While transcriptionally different from their murine counterparts64, DAAs from individuals with AD have been subclassified into 8 different clusters, one of which exhibits signatures of immune signaling including transforming growth factor beta 1 (TGFB1) activation57. Of note, human DAAs overexpress APOE as well as glypican 4 (GPC4), a secreted factor that has been detected in post-mortem brains from patients with APOE4-associated AD70,71 and may contribute to disease progression upon direct interaction with APOE4 and consequent tau hyperphosphorylation57. Supporting the pathogenic role of this mechanism, Apoe4 deletion from astrocytes limits disease progression in P301S mice54. Thus, pro-inflammatory signaling elicited by microglia may promote AD progression also via astrocytes.
Yet another non-neuronal cell type involved in AD are so-called disease-associated oligodendrocytes (DOLs). A study integrating multiple datasets from mouse models of NDs and post-mortem data from ND patients identified three different oligodendrocyte activation states: disease-associated 1 (DA1), DA2 and interferon (IFN)-associated72. Intriguingly, not only IFN-associated DOLs but also DA1 DOLs exhibit upregulation of multiple genes involved in innate and adaptive immunity, including multiple cytokine- and complement-encoding genes as well as genes coding for MHC Class I and Class II molecules72. At least some of these DOL signatures are not restricted to AD, but can also be documented in other NDs and neuroinflammatory disorders, suggesting a common response to severe pathological conditions73. Of note, DOLs have TREM2-independent transcriptional responses to neurodegenerative conditions that resembles those of DAAs49, including the overexpression of stress-responsive proteins such as serpin family A member 3 (SERPINA3)73. That said the transcriptional profile of DOLs from individuals with AD considerably differs from that of mouse AD models72.
Importantly, not only brain-resident cells engaging in innate immune signaling, but also newly recruited immune cells have been shown to contribute to AD pathogenesis. For instance, neutrophil infiltration has been documented in individuals with various NDs including AD, a finding that has been mechanistically linked with reduced cerebral blood flow in APP-PS1 mice, 5XFAD mice, as well as mice expressing pathogenic variants of APP, PS1 and tau (namely, 3xTg mice). In these models, blood flow and short-term memory function rapidly improve when cerebral perfusion is restored by preventing neutrophil adhesion74,75. Along similar lines, several studies have demonstrated infiltration of the brain parenchyma by CD4+ and CD8+ T cells (which orchestrate and execute antigen-specific immune responses, respectively) in patients with AD76,77 and in animal models of the disease49,78. In this setting, extravascular cytotoxic CD8+ T cell abundance appears to correlate with disease stage, indicating a potential role for adaptive immunity in the pathogenesis of AD79,80,81. Similar findings have been obtained in APP-PS1 and 5XFAD mice81. Importantly, in this latter setting CD8+ T cell infiltration of the brain parenchyma could be mechanistically linked to the microglia, and not only CD8+ T cell depletion but also interference with CD8+ functions by interferon gamma (IFNG) or programmed cell death 1 (PDCD1, best known as PD-1) blockage mediated considerable neuroprotective effects81, potentially linked to the reversal of CD8+ T cell exhaustion82. Further supporting a link between CD8+ T cell activity and the pathogenesis of AD, peripheral blood mononuclear cells (PBMCs) from patients with AD are enriched in CD8+CD45RA+ T effector memory (TEMRA) cells displaying transcriptional signatures of activation, and their abundance negatively correlated with cognition83.
Conversely, the actual impact of helper CD4+ T cells on AD progression remains to be formally established. Indeed, administration of Aβ-specific type 1 (TH1) and type 17 (TH17) CD4+ T cells (two specialized populations of CD4+ T cells characterized by specific secretory profiles) reportedly exacerbates memory impairment and amyloid deposition in APP-PS1 mice84. Moreover, CD4+ T cell depletion appears to improve Aβ clearance and cognitive performance in 5XFAD mice85. However, CD4+ T cell depletion has also been associated with accelerated cognitive decline with no impact on amyloid pathology in APP-PS1 mice86. At least theoretically, these apparently contrasting findings may relate to the considerable phenotypic and functional diversity of CD4+ T cells, encompassing a highly reactive compartment as well as immunosuppressive subpopulations such as CD4+CD25+FOXP3+ regulatory T (TREG) cells87,88. Indeed, TREG cells have consistently been shown to limit AD progression in mouse models of the disease89,90,91.
Interestingly, multiple microglia–T cell interactions have been documented in patients with AD and/or mouse models thereof, including (but not limited to) TCR responses to MHC Class II-restricted peptides92. That said, single-cell analyses of T cells infiltrating the brain of mice affected by amyloid, tau or combined (amyloid and tau) pathology suggest that T cell reactivity is not influenced by TREM2 expression in the DAM49. Taken together, these observations suggest that while the DAM may drive pathogenic T cell responses during AD progression, such responses (at least initially) may not impinge on the APOE-TREM2 signalling axis. Recently, B cells (a population of lymphoid cells specialized in antigen presentation and antibody production) have also been mechanistically implicated in the pathogenesis of AD93. Specifically, 3×Tg mice have been shown to exhibit not only an expanded B cell comportment in the periphery, but also accrued B cell accumulation in the brain parenchyma associated with immunoglobulin deposition at amyloid plaques93. In the same setting, B cell depletion at disease onset appears to reduce amyloid accumulation, limit hippocampal microglial activation and overall decelerate disease progression93.
In summary, the pathogenesis of AD involves a complex neuroinflammatory reaction involving brain-resident cells as well as newly recruited immune cells that ultimately promote neurotoxicity coupled to cognitive disorders (Fig. 1).
Parkinson’s disease
PD is the most prevalent ND that results in disordered movement, affecting 6–7 million individuals worldwide3. While most PD cases are idiopathic, a familial form of the disease has been associated with mutations in > 20 genes, including parkin RBR E3 ubiquitin protein ligase (PRKN), PTEN-induced kinase 1 (PINK1), both of which encode component of the molecular apparatus that removes dysfunctional mitochondria (so-called mitophagy)94, leucine-rich repeat kinase 2 (LRRK2), encoding a multifunctional kinase, and synuclein alpha (SNCA)95. The main pathological feature of PD is the degeneration of dopaminergic neurons in the substantia nigra (SN) involving the intraneuronal accumulation of SNCA aggregates called Lewy bodies3. Of note, SNCA aggregates have also been documented in the gastrointestinal tract of PD patients up to 20 years prior to their diagnosis96, and the administration of preformed SNCA fibrils into the duodenal and pyloric muscularis layer promotes PD development in mice97. These observations point to the existence of a gut-to-brain axis that contributes to the spread of pathogenic Lewy bodies to the central nervous system.
While neuronal dysfunction coupled with oxidative stress has a major role in the pathogenesis of PD, variations in numerous genes encoding key components of the innate and adaptive immune system have been associated with an increased risk for PD, including an MHC Class II haplotype that is displayed by ~15% of the population (namely, HLA-DRB1)98. Moreover, multiple genetic loci associated with an increased risk for PD appear to also predispose to some autoimmune and inflammatory diseases, such as Crohn’s disease99. Of note, PD patients often exhibit elevations in the circulating or cerebrospinal levels of cytokines such as TNF, interleukin 1 beta (IL1B), IL2 and IL10100,101. In line with this notion, microglial activation is a characteristic finding in the SN of post-mortem brains from patients with PD feature of the substantia nigra in post-mortem human brains with PD77,102, and the active microglia has been shown to actively engage in pro-inflammatory signalling via various molecular platform including (but not limited to) the NF-κB, inflammasome, JAK/STAT and Toll-like receptor (TLR) signaling103,104,105, at least in some settings as a direct consequence of tau accumulation106. Importantly, multiple pharmacological strategies aimed at interrupting these signal transduction cascades have been shown to decelerate PD progression in animal models, including rats intracerebrally administered with an SNCA-encoding adenovirus or treated with the PD-inducer rotenone103,104,105. Together with the fact that significant microgliosis has been documented in areas not showing significant neuronal death in post-mortem brains from patients with PD107,108,109 and with kinetic data from rodent models of PD110, these findings suggest that inflammatory microglial activation precedes and promotes the demise of dopaminergic neurons that characterize PD. At least in part, such a neurotoxic response involves the microglia-driven conversion of astrocytes to a pathogenic state, as mechanistically demonstrated with a small molecule that prevents this conversion (i.e., NLY01) in mice expressing a pathogenic variant of SNCA or administered intracerebrally with preformed SNCA fibrils111.
Further supporting a link between inflammation and the pathogenesis of PD, SNCA has been shown to promote microglial activation in an MHC Class II-dependent manner, culminating with the initiation of a pathogenic CD4+ T cell response112. In line with this notion, SNCA overexpression in the mouse midbrain results in the upregulation of MHC Class II molecules on myeloid cells coupled with abundant infiltration of IFNG-producing CD4+ and CD8+ T cells113, a process that at least in part involves so-called border associated macrophages (BAMs)114. However, while the absence of CD3+ T cells or CD4+ T cells reportedly decelerates PD progression and ameliorate behavioral symptoms in mice treated with the PD driver 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the same does not hold true for the selective absence of CD8+ T cells102. That said, CD8+ T cell infiltration has been documented in the SN from pre-symptomatic PD patients, de facto preceding dopaminergic neuron loss and SNCA pathology115. Moreover, patients with overt PD exhibit: (1) a reduction in the levels of circulating naïve T cells and TREG cells116, (2) an increase in the ratio of IFNG- over IL4-producing CD4+ T cells in the periphery117, and (3) circulating T cells responding to SNCA-derived peptides118, an autoreactivity that appears to develop even prior to clinical manifestations of the disease119. Finally, results from Snca−/− mice indicate that SNCA is also required for the development of normal inflammatory and antigen-specific responses to intraperitoneal bacteria120, further strengthening the links between PD and immunity.
In summary, PD appears to involve a variety of innate and adaptive immune processes that culminate with the loss of dopaminergic neurons in the SN and the consequent motor symptoms (Fig. 2).
Huntington’s disease
HD is an autosomal dominant neurological disorder caused by an aberrant expansion of CAG triplets in exon 1 of HTT, resulting in a long polyglutamine tract that disrupts HTT cellular functions and causes widespread neurotoxicity starting from the neostriatum3. Clinical HD manifestations include progressive cognitive, motor and behavioral impairments3.
Similar to AD and PD, HD is also characterized by microgliosis, both in humans121,122,123 and in mouse models of the disease such as R6/2 mice124,125,126. Moreover, HD resembles AD and PD in that inflammatory microglial activation constitutes an early event in the pathogenesis of disease as it has been documented in post-mortem brain samples from patients with pre-symptomatic HD126,127. Of note, HD-associated microgliosis has also been linked with alterations in circulating myeloid cells and cytokines, and at least some of these changes could be detected in mutant HTT carriers prior to clinical manifestations of the disease128,129.
Several lines of evidence implicate HTT-driven inflammatory microglial activation in the pathogenesis of HD. First, microglial depletion using an inhibitor of colony-stimulating factor 1 receptor (CSF1R) reduces mutant HTT accumulation and prevents striatal atrophy in R6/2 mice130. Second, the establishment of mouse chimeras incorporating human microglial cells expressing mutant HTT promotes motor impairment and neuronal dysfunction in the striatum, while the contrary is true when the human microglia expresses wild-type HTT131,132. Third, mutant HTT expression in microglial cells is sufficient to drive microgliosis and elicit neurodegeneration133.
HD-associated HTT mutations also affect astrocytic and oligodendrocytic cells. For instance, mutant HTT expression in microglia has been shown to deregulate the expression of multiple cell lineage-specific genes in astrocytes from R6/2 mice and zQ175 mice (another mouse model of HD)134. Moreover, data from multiple HD rodent models as well as from post-mortem HD brain tissues suggest that the accumulation of mutant HTT in the nucleus is way more frequent in astrocytes and oligodendrocytes than in the microglia135,136. Corroborating the pathogenic effect of mutant HTT accumulation in cells other than the microglia, selective inactivation of mutant HTT in NG2+ oligodendrocyte progenitors prevents myelin abnormalities and certain behavioral deficits in HD mice137. Moreover, the cell-specific downregulation of mutant HTT from astrocytes or neurons coupled with modern sequencing technologies reveal that astrocyte dysfunction has a smaller impact on the neuronal transcriptome than neuron dysfunction has on the astrocytic one138. In line with this notion, at least three different transcriptional clusters of disease-associated astrocytes have been documented in post-mortem cingulate cortex samples from patients with HD, including a cluster with prominent stress-responsive and reactive transcriptional profile139. Transcriptional data from two distinct mouse models of HD and post-mortem HD brains also delineate the existence of shared transcriptional alterations linked to astrocytic dysfunction that can be corrected by limiting mutant HTT expression140. Taken together, these observations highlight the prominent role of inflammatory microglial activation as a driver of cellular dysfunction in the context of HD.
Of note, mutant HTT levels in circulating leukocytes have been shown not only to positively correlate with disease burden in patients with HD, but also to elicit immunological dysfunction coupled with increased TNF and IL8 secretion downstream of altered NF-κB functions141. In this setting, HTT silencing by RNA interference was sufficient to reverse secretory and transcriptional alterations141. Whether such an intervention would modify disease course in mouse models of HD, though, remains to be further investigated. That said, signs of both central and peripheral immune activation have been documented for both dendritic cells (DCs)142 and macrophages143 in R6/2 mice and zQ175 mice. Moreover, mutant HTT carriers exhibit a cerebrospinal T cell compartment characterized by increased IL17 expression coupled with the acquisition of a TH17 polarization and elevated IL7 consumption prior to symptom onset, and the abundance of cerebrospinal TH17 cells negatively correlates with disease progression144. These latter observations suggest that T cells may be involved in the early pathogenesis of HD and hence that limiting T cell responses may delay the onset of symptomatic HD.
Thus, similar to AD and PD, HD appears to develop in the context of complex innate and adaptive immune responses that manifest both centrally and in the periphery (Fig. 3).
Others
Dementia with Lewy bodies
Dementia with Lewy bodies (DLB) is a prevalent form of dementia in the elderly that is defined by cognitive impairment coupled with visual hallucinations, parkinsonism, sleep behavior disorders, as well as autonomic and psychiatric dysfunction145. Of note, both AD and PD not only share familiar risk factors with DLB, notably genetic variants of APOE and SNCA145, but also exhibit similar clinical manifestations, making differential diagnosis problematic146,147. Moreover, at least a fraction of DLB cases share with AD the deposit of Aβ plaques as well as tau hyperphosphorylation, and with PD the accumulation of SNCA aggregates (Lewy bodies), although this does not often involve the SN, but instead affects basal ganglia and the cerebral cortex145. Finally, DLB has been associated with a history of traumatic brain injury (TBI), at least potentially linked to neuroinflammation148,149. However, the pathogenesis of DLB remains poorly understood, partly due to a lack of precise cellular and animal models of the disease.
Analysis of post-mortem brains from patients with DLB revealed diffuse cerebral inflammation and an increased number of microglial cells in the proximity of Lewy bodies150, as well as increased levels of proinflammatory cytokines such as IL6 coupled to the downregulation of neurotrophic factors151. Similar to the case of AD, microgliosis as associated with DLB appears to occur early during disease pathogenesis152 and to decline over time as cognitive impairment emerges153. Moreover, DLB has been associated with an increase in the circulating levels of several proinflammatory cytokines including IL2, IL17A and C-C motif chemokine ligand 20 (CCL20) along with decreased IL8 concentrations153, pointing to an involvement of both innate and adaptive immune mechanisms in the pathogenesis of the disease.
Further supporting a pathogenic role for immune effectors in the progression of DLB, CD4+ (but not CD8+) T cells have been shown to infiltrate the brain parenchyma of patients with DLB and SNCA-expressing mice, a rodent model of the disease that also manifests intracranial accumulation of natural killer T (NKT) cells154, a small lymphoid cell population with potent reactive traits155,156. Intriguingly, DLB-associated CD4+ T cell brain infiltration appears to be maximal in the proximity of blood vessels154, and these cells appear to acquire a TH17 phenotype coupled with pathogenic IL17A secretion in the cerebrospinal fluid downstream of C-X-C motif chemokine ligand 12 (CXCL12)-driven, C-X-C motif chemokine receptor 4 (CXCR4)-mediated recruitment157, a potent chemotactic signalling axis158.
These findings suggest that, while the precise etiology of DLB remains to be clarified, adaptive immune effectors including IL17A-secreting CD4+ T cells may contribute to DLB establishment and progression.
Frontotemporal dementia
Frontotemporal dementia (FTD) is an early-onset neurodegenerative disorder driven by a progressive atrophy of the frontal and temporal lobes and characterized by alterations in behavior, impulse control, personality, and language159. Pathologically, FTD is characterized by abnormal accumulations of TAR DNA binding protein (TARDBP), hyperphosphorylated tau or FET proteins, which encompass EWS RNA binding protein 1 (EWSR1), TATA-box binding protein associated factor 15 (TAF15) and FUS RNA binding protein (FUS)159. Mutations in C9orf72-SMCR8 complex subunit (C9Orf72), MAPT, TREM2 and granulin precursor (GRN) have been associated with familial variants of the disease160,161,162,163, but sporadic FTD accounts for > 60% of FTD cases164. Interestingly, FTD-related mutations have also been associated with an increased risk for autoimmune conditions165,166, pointing to a potential role for neuroinflammation in the pathogenesis of this ND.
In line with this possibility, FTD has been consistently associated with microgliosis and neuroinflammation in patients167,168,169. Moreover, individuals affected by FTD exhibit increased cerebrospinal levels of multiple pro-inflammatory cytokines including (but not limited to) IL2, IL12, IL17A, TNF, TGFB1 and CXCL1, at least in some patient cohorts positively correlated with disease severity170,171,172. Interestingly, cerebrospinal alterations in cytokine levels appear to vary in sporadic vs familial FTD cases173, but the causes underlying the observations remain to be determined. One study also identified a decrease in circulating B cells in patients with FTD174, but these findings await validation in larger patient cohorts.
Of note, Grn−/− mice exhibit pro-inflammatory microglial activation downstream of NF-κB signaling175,176 coupled with the acquisition of an FTD-associated microglial state that: (1) is different from the AD- and ALS-associated DAMs, and (2) actively supports neurotoxic TARDBP granule deposition177, at least in part as a consequence of lysosomal dysfunction178. Along similar lines, mice expressing an FTD-associated TREM2 mutant exhibit brain-wide alterations including a delayed resolution of neuroinflammatory responses and a reduction of cerebral blood flow that may support disease progression179.
Vascular dysfunction and astrocytosis have also been observed in the frontal and temporal lobes of patients with FTD180. Specifically, a highly conserved astrocytic phenotype promoting synaptic degeneration and TARDBP neuropathy has been identified in the thalamus and frontal cortex of patients with GRN-associated FTD and Grn−/− mice181, pointing to a central role for these cells in FTD progression.
In summary, FTD also involves an immunological component, although it remains poorly characterized. Additional studies are required to elucidate innate and potentially adaptive immune mechanisms involved in the pathogenesis of FTD.
Conclusions
While most central NDs appear to originate from genetic or environmental alterations of cellular homeostasis in the brain parenchyma, it is now clear that such perturbations are accompanied by the activation of innate and (at least in some cases) adaptive immune effector mechanisms that contribute to disease pathogenesis. As abundantly discussed herein, multiple NDs are associated with mutations in genes encoding components of the innate or adaptive immune system, such as TREM229,30,31 or HLA-DRB135. Moreover, hitherto unrecognized connections are emerging between central ND susceptibility genes, such as SNCA, and core immunological functions, such as the development of normal innate and adaptive immune reactions to bacterial challenges120. Finally, patients affected by numerous NDs including AD, PD, HD, DLB and FTD exhibit shifts in the circulating levels of pro-inflammatory cytokines or peripheral immune populations, further supporting a pathogenic role for altered immune responses in the central nervous system in the progression of NDs. With a few exceptions including the robust implication of CD4+ in disease pathogenesis in mouse models of DLB157, most of the current links between immunological mechanisms and ND pathogenesis rely on observational and correlative rather than mechanistic experimental setups. While at least partially this reflects the limited number of rodent models that recapitulate the emergence and progression of NDs in humans, it will be important to harness currently available models to implement antibody-mediated depletion, pharmacological inhibition or genetic deletion/downregulation experiments to mechanistically link altered immune functions to ND pathogenesis and potentially identify novel targets for therapeutic interventions.
In the era of cancer immunotherapy (Box 2), the data summarized herein point indeed to the possibility of harnessing immunomodulatory agents beyond general anti-inflammatory and immunosuppressive drugs such as corticosteroids for the management of multiple NDs. While as mentioned above preclinical data in support of this possibility suffer from an overall observational nature, it is still tempting to postulate that currently approved therapeutics affecting immune functions may be beneficial for at least some patients with NDs. For instance, circulating IL17A elevations and/or polarization of the CD4+ T cell compartment toward a TH17 profile have been detected in patients with PD144, DLB153 and FTD172, and no less than three distinct IL17A blockers are currently available for the treatment of inflammatory conditions such as psoriasis182. Along similar lines, TREG cells have been demonstrated to limit disease progression in multiple mouse models of AD89,90,91, pointing to adoptive TREG transfer as an intriguing possibility to control AD progression in humans. Finally, PD-1 blockage has been associated with neuroprotective effects in mouse models of AD81, and multiple immune checkpoint inhibitors targeting PD-1 or its main ligand CD274 (PD-L1) are currently licensed for use in patients with various malignancies24.
Importantly, the use of immunomodulatory agents for the management of NDs has begun to be explored in the clinic. Specifically, a TREM2-targeting monoclonal antibody (AL002) is currently being assessed in patients with AD (NCT05744401)39, while an inflammasome inhibitor (RO7486967) is under investigation in individuals with PD (NCT05924243). Whether these or other immunomodulators are effective and will ultimately be approved for use in humans, however, remains to be established.
In summary, while additional work is required to elucidate the actual therapeutic potential of immunotherapy for patients with central NDs, both innate and immune dysfunctions have been documented during the progression of AD, PD, HD, DLB and FTD. It will be important to obtain further mechanistic insights into the immunological aspects of human degeneration in existing and newly developed rodent ND models to develop disease-modifying treatment options for these patient populations.
References
Knopman, D. S. et al. Alzheimer disease. Nat. Rev. Dis. Prim. 7, 33 (2021).
Filippi, M. et al. Multiple sclerosis. Nat. Rev. Dis. Prim. 4, 43 (2018).
Poewe, W. et al. Parkinson disease. Nat. Rev. Dis. Prim. 3, 17013 (2017).
Myszczynska, M. A. et al. Applications of machine learning to diagnosis and treatment of neurodegenerative diseases. Nat. Rev. Neurol. 16, 440–456 (2020).
Congdon, E. E., Ji, C., Tetlow, A. M., Jiang, Y. & Sigurdsson, E. M. Tau-targeting therapies for Alzheimer disease: Current status and future directions. Nat. Rev. Neurol. 19, 715–736 (2023).
Akçimen, F. et al. Amyotrophic lateral sclerosis: Translating genetic discoveries into therapies. Nat. Rev. Genet. 24, 642–658 (2023).
Elkouzi, A., Vedam-Mai, V., Eisinger, R. S. & Okun, M. S. Emerging therapies in Parkinson disease - repurposed drugs and new approaches. Nat. Rev. Neurol. 15, 204–223 (2019).
van Dyck, C. H. et al. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 388, 9–21 (2023).
Bates, G. P. et al. Huntington disease. Nat. Rev. Dis. Prim. 1, 15005 (2015).
Ropers, H. H. Genetics of early onset cognitive impairment. Annu. Rev. Genom. Hum. Genet. 11, 161–187 (2010).
Hou, Y. et al. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15, 565–581 (2019).
Reitz, C., Pericak-Vance, M. A., Foroud, T. & Mayeux, R. A global view of the genetic basis of Alzheimer disease. Nat. Rev. Neurol. 19, 261–277 (2023).
Hannan, A. J. Tandem repeats mediating genetic plasticity in health and disease. Nat. Rev. Genet. 19, 286–298 (2018).
Goutman, S. A., Savelieff, M. G., Jang, D. G., Hur, J. & Feldman, E. L. The amyotrophic lateral sclerosis exposome: recent advances and future directions. Nat. Rev. Neurol. 19, 617–634 (2023).
Hampel, H. & Lista, S. Alzheimer disease: from inherited to sporadic AD-crossing the biomarker bridge. Nat. Rev. Neurol. 8, 598–600 (2012).
Needham, B. D., Kaddurah-Daouk, R. & Mazmanian, S. K. Gut microbial molecules in behavioural and neurodegenerative conditions. Nat. Rev. Neurosci. 21, 717–731 (2020).
Travagli, R. A., Browning, K. N. & Camilleri, M. Parkinson disease and the gut: new insights into pathogenesis and clinical relevance. Nat. Rev. Gastroenterol. Hepatol. 17, 673–685 (2020).
Blackhurst, B. M. & Funk, K. E. Viral pathogens increase risk of neurodegenerative disease. Nat. Rev. Neurol. 19, 259–260 (2023).
Qiu, C. & Fratiglioni, L. A major role for cardiovascular burden in age-related cognitive decline. Nat. Rev. Cardiol. 12, 267–277 (2015).
Tan, E. K. et al. Parkinson disease and the immune system - associations, mechanisms and therapeutics. Nat. Rev. Neurol. 16, 303–318 (2020).
Rodríguez Murúa, S., Farez, M. F. & Quintana, F. J. The immune response in multiple sclerosis. Annu. Rev. Pathol. 17, 121–139 (2022).
Adamo, L., Rocha-Resende, C. & Mann, D. L. The emerging role of B lymphocytes in cardiovascular disease. Annu. Rev. Immunol. 38, 99–121 (2020).
Markousis-Mavrogenis, G. et al. Immunomodulation and immunopharmacology in heart failure. Nat. Rev. Cardiol. 1, 119–149 (2024).
Kroemer, G., Chan, T. A., Eggermont, A. M. M & Galluzzi, L. Immunosurveillance in clinical cancer management. CA Cancer J. Clin. In Press https://doi.org/10.3322/caac.21818 (2024). Epub ahead of print.
Prinz, M., Masuda, T., Wheeler, M. A. & Quintana, F. J. Microglia and Central Nervous System-associated Macrophages-from Origin To Disease Modulation. Annu. Rev. Immunol. 39, 251–277 (2021).
Klotz, L., Antel, J. & Kuhlmann, T. Inflammation in multiple sclerosis: Consequences for remyelination and disease progression. Nat. Rev. Neurol. 19, 305–320 (2023).
Vahsen, B. F. et al. Non-neuronal cells in amyotrophic lateral sclerosis - from pathogenesis to biomarkers. Nat. Rev. Neurol. 17, 333–348 (2021).
Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).
Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).
Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).
Sims, R. et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1384 (2017).
Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 41, 1094–1099 (2009).
Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet. 43, 429–435 (2011).
Naj, A. C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat. Genet. 43, 436–441 (2011).
Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013).
Kunkle, B. W. et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat. Genet. 51, 414–430 (2019).
Parhizkar, S. et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat. Neurosci. 22, 191–204 (2019).
Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).
Wang, S. et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J. Exp. Med. 217, e20200785 (2020).
Jiang, T. et al. TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice. Neuropharmacology 105, 196–206 (2016).
Leyns, C. E. G. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl. Acad. Sci. USA 114, 11524–11529 (2017).
Gratuze, M. et al. TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4. Neuron 111, 202–219.e207 (2023).
Leyns, C. E. G. et al. TREM2 function impedes tau seeding in neuritic plaques. Nat. Neurosci. 22, 1217–1222 (2019).
Gratuze, M. et al. Activated microglia mitigate Aβ-associated tau seeding and spreading. J. Exp. Med. 218, e20210542 (2021).
Liu, Z. et al. Lipid-associated macrophages in the tumor-adipose microenvironment facilitate breast cancer progression. Oncoimmunology 11, 2085432 (2022).
Schlepckow, K. et al. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol. Med. 12, e11227 (2020).
Zhao, N. et al. Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia. J. Exp. Med. 219, e20212479 (2022).
Sayed, F. A. et al. Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy. Proc. Natl. Acad. Sci. USA 115, 10172–10177 (2018).
Lee, S. H. et al. TREM2-independent oligodendrocyte, astrocyte, and T cell responses to tau and amyloid pathology in mouse models of Alzheimer disease. Cell Rep. 37, 110158 (2021).
Keren-Shaul, H. et al. A unique Microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e1217 (2017).
Sala Frigerio, C. et al. The major risk factors for Alzheimer’s disease: age, sex, and genes modulate the microglia response to Aβ plaques. Cell Rep. 27, 1293–1306.e1296 (2019).
Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581.e569 (2017).
Shi, Y. et al. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J. Exp. Med. 216, 2546–2561 (2019).
Wang, C. et al. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron 109, 1657–1674.e1657 (2021).
Koutsodendris, N. et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat. Aging 3, 275–296 (2023).
Srinivasan, K. et al. Alzheimer’s patient microglia exhibit enhanced aging and unique transcriptional activation. Cell Rep. 31, 107843 (2020).
Grubman, A. et al. A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat. Neurosci. 22, 2087–2097 (2019).
Streit, W. J., Sammons, N. W., Kuhns, A. J. & Sparks, D. L. Dystrophic microglia in the aging human brain. Glia 45, 208–212 (2004).
Streit, W. J., Braak, H., Xue, Q. S. & Bechmann, I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol. 118, 475–485 (2009).
Lopes, K. O., Sparks, D. L. & Streit, W. J. Microglial dystrophy in the aged and Alzheimer’s disease brain is associated with ferritin immunoreactivity. Glia 56, 1048–1060 (2008).
Bachstetter, A. D. et al. Disease-related microglia heterogeneity in the hippocampus of Alzheimer’s disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol. Commun. 3, 32 (2015).
Shahidehpour, R. K. et al. Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain. Neurobiol. Aging 99, 19–27 (2021).
Neumann, P., Lenz, D. E., Streit, W. J. & Bechmann, I. Is microglial dystrophy a form of cellular senescence? An analysis of senescence markers in the aged human brain. Glia 71, 377–390 (2023).
Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).
Richetin, K. et al. Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer’s disease. Nat. Neurosci. 23, 1567–1579 (2020).
Jack, C. R. Jr et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128 (2010).
Chun, H. et al. Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer’s disease via H(2)O(2)(-) production. Nat. Neurosci. 23, 1555–1566 (2020).
Zamanian, J. L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012).
Matias, I., Morgado, J. & Gomes, F. C. A. Astrocyte heterogeneity: impact to brain aging and disease. Front. Aging Neurosci. 11, 59 (2019).
Habib, N. et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23, 701–706 (2020).
Saroja, S. R., Gorbachev, K., Julia, T., Goate, A. M. & Pereira, A. C. Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation. Proc. Natl. Acad. Sci. USA 119, e2108870119 (2022).
Pandey, S. et al. Disease-associated oligodendrocyte responses across neurodegenerative diseases. Cell Rep. 40, 111189 (2022).
Kenigsbuch, M. et al. A shared disease-associated oligodendrocyte signature among multiple CNS pathologies. Nat. Neurosci. 25, 876–886 (2022).
Zenaro, E. et al. Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat. Med. 21, 880–886 (2015).
Cruz Hernández, J. C. et al. Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models. Nat. Neurosci. 22, 413–420 (2019).
Merlini, M., Kirabali, T., Kulic, L., Nitsch, R. M. & Ferretti, M. T. Extravascular CD3+ T cells in brains of Alzheimer disease patients correlate with Tau but not with amyloid pathology: an immunohistochemical study. Neurodegener. Dis. 18, 49–56 (2018).
McGeer, P. L., Itagaki, S., Boyes, B. E. & McGeer, E. G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38, 1285–1291 (1988).
Laurent, C. et al. Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy. Brain 140, 184–200 (2017).
Togo, T. et al. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J. Neuroimmunol. 124, 83–92 (2002).
Unger, M. S. et al. CD8(+) T-cells infiltrate Alzheimer’s disease brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice. Brain Behav. Immun. 89, 67–86 (2020).
Chen, X. et al. Microglia-mediated T-cell infiltration drives neurodegeneration in tauopathy. Nature 615, 668–677 (2023).
Su, W. et al. CXCR6 orchestrates brain CD8(+) T cell residency and limits mouse Alzheimer’s disease pathology. Nat. Immunol. 24, 1735–1747 (2023).
Gate, D. et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399–404 (2020).
Machhi, J. et al. CD4+ effector T cells accelerate Alzheimer’s disease in mice. J. Neuroinflammation 18, 272 (2021).
Baruch, K. et al. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer’s disease pathology. Nat. Commun. 6, 7967 (2015).
Mittal, K. et al. CD4 T cells induce a subset of MHCII-Expressing Microglia that attenuates Alzheimer pathology. iScience 16, 298–311 (2019).
Tanchot, C. et al. Tumor-infiltrating regulatory T cells: phenotype, role, mechanism of expansion in situ and clinical significance. Cancer Microenviron. 6, 147–157 (2013).
Trujillo-Ochoa, J. L., Kazemian, M. & Afzali, B. The role of transcription factors in shaping regulatory T cell identity. Nat. Rev. Immunol. 23, 842–856 (2023).
Stym-Popper, G. et al. Regulatory T cells decrease C3-positive reactive astrocytes in Alzheimer-like pathology. J. Neuroinflamm 20, 64 (2023).
Yang, H. et al. Adoptive therapy with amyloid-β specific regulatory T cells alleviates Alzheimer’s disease. Theranostics 12, 7668–7680 (2022).
Baek, H. et al. Neuroprotective effects of CD4+CD25+Foxp3+ regulatory T cells in a 3xTg-AD Alzheimer’s disease model. Oncotarget 7, 69347–69357 (2016).
Schetters, S. T. T., Gomez-Nicola, D., Garcia-Vallejo, J. J. & Van Kooyk, Y. Neuroinflammation: Microglia and T cells get ready to Tango. Front. Immunol. 8, 1905 (2017).
Kim, K. et al. Therapeutic B-cell depletion reverses progression of Alzheimer’s disease. Nat. Commun. 12, 2185 (2021).
Vargas, J. N. S., Hamasaki, M., Kawabata, T., Youle, R. J. & Yoshimori, T. The mechanisms and roles of selective autophagy in mammals. Nat. Rev. Mol. Cell Biol. 24, 167–185 (2023).
Trinh, J. & Farrer, M. Advances in the genetics of Parkinson disease. Nat. Rev. Neurol. 9, 445–454 (2013).
Stokholm, M. G., Danielsen, E. H., Hamilton-Dutoit, S. J. & Borghammer, P. Pathological α-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann. Neurol. 79, 940–949 (2016).
Kim, S. et al. Transneuronal propagation of pathologic α-Synuclein from the gut to the brain models Parkinson’s disease. Neuron 103, 627–641.e627 (2019).
Saiki, M. et al. Association of the human leucocyte antigen region with susceptibility to Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 81, 890–891 (2010).
Witoelar, A. et al. Genome-wide Pleiotropy between Parkinson disease and autoimmune diseases. JAMA Neurol. 74, 780–792 (2017).
Koziorowski, D., Tomasiuk, R., Szlufik, S. & Friedman, A. Inflammatory cytokines and NT-proCNP in Parkinson’s disease patients. Cytokine 60, 762–766 (2012).
Williams-Gray, C. H. et al. Serum immune markers and disease progression in an incident Parkinson’s disease cohort (ICICLE-PD). Mov. Disord. 31, 995–1003 (2016).
Brochard, V. et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest. 119, 182–192 (2009).
Codolo, G. et al. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLoS One 8, e55375 (2013).
Qin, H. et al. Inhibition of the JAK/STAT pathway protects against α-Synuclein-induced neuroinflammation and dopaminergic neurodegeneration. J. Neurosci. 36, 5144–5159 (2016).
Sarkar, S. et al. Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson’s disease. NPJ Parkinsons Dis. 3, 30 (2017).
Ising, C. et al. NLRP3 inflammasome activation drives tau pathology. Nature 575, 669–673 (2019).
Imamura, K. et al. Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol. 106, 518–526 (2003).
Ouchi, Y. et al. Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann. Neurol. 57, 168–175 (2005).
Gerhard, A. et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol. Dis. 21, 404–412 (2006).
Watson, M. B. et al. Regionally-specific microglial activation in young mice over-expressing human wildtype alpha-synuclein. Exp. Neurol. 237, 318–334 (2012).
Yun, S. P. et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat. Med. 24, 931–938 (2018).
Harms, A. S. et al. MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J. Neurosci. 33, 9592–9600 (2013).
Williams, G. P. et al. CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson’s disease. Brain 144, 2047–2059 (2021).
Schonhoff, A. M. et al. Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease. Nat. Commun. 14, 3754 (2023).
Galiano-Landeira, J., Torra, A., Vila, M. & Bové, J. CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson’s disease. Brain 143, 3717–3733 (2020).
Saunders, J. A. et al. CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J. Neuroimmune Pharm. 7, 927–938 (2012).
Baba, Y., Kuroiwa, A., Uitti, R. J., Wszolek, Z. K. & Yamada, T. Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat. Disord. 11, 493–498 (2005).
Sulzer, D. et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature 546, 656–661 (2017).
Lindestam Arlehamn, C. S. et al. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease. Nat. Commun. 11, 1875 (2020).
Alam, M. M. et al. Alpha synuclein, the culprit in Parkinson disease, is required for normal immune function. Cell Rep. 38, 110090 (2022).
Vonsattel, J. P., Keller, C. & Del Pilar Amaya, M. Neuropathology of Huntington’s disease. Handb. Clin. Neurol. 89, 599–618 (2008).
Sapp, E. et al. Early and progressive accumulation of reactive microglia in the Huntington disease brain. J. Neuropathol. Exp. Neurol. 60, 161–172 (2001).
Pavese, N. et al. Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Neurology 66, 1638–1643 (2006).
Ma, L., Morton, A. J. & Nicholson, L. F. Microglia density decreases with age in a mouse model of Huntington’s disease. Glia 43, 274–280 (2003).
Simmons, D. A. et al. Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington’s disease. Glia 55, 1074–1084 (2007).
Politis, M. et al. Microglial activation in regions related to cognitive function predicts disease onset in Huntington’s disease: a multimodal imaging study. Hum. Brain Mapp. 32, 258–270 (2011).
Tai, Y. F. et al. Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain 130, 1759–1766 (2007).
Chang, K. H., Wu, Y. R., Chen, Y. C. & Chen, C. M. Plasma inflammatory biomarkers for Huntington’s disease patients and mouse model. Brain Behav. Immun. 44, 121–127 (2015).
Miller, J. R. et al. RNA-Seq of Huntington’s disease patient myeloid cells reveals innate transcriptional dysregulation associated with proinflammatory pathway activation. Hum. Mol. Genet. 25, 2893–2904 (2016).
Crapser, J. D. et al. Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington’s disease. Brain 143, 266–288 (2020).
Osipovitch, M. et al. Human ESC-derived chimeric mouse models of huntington’s disease reveal cell-intrinsic defects in glial progenitor cell differentiation. Cell Stem Cell 24, 107–122.e107 (2019).
Benraiss, A. et al. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease. Nat. Commun. 7, 11758 (2016).
Crotti, A. et al. Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat. Neurosci. 17, 513–521 (2014).
Benraiss, A. et al. Cell-intrinsic glial pathology is conserved across human and murine models of Huntington’s disease. Cell Rep. 36, 109308 (2021).
Jansen, A. H. et al. Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell-type-specific. Glia 65, 50–61 (2017).
Huang, B. et al. Mutant huntingtin downregulates myelin regulatory factor-mediated myelin gene expression and affects mature oligodendrocytes. Neuron 85, 1212–1226 (2015).
Ferrari Bardile, C. et al. Intrinsic mutant HTT-mediated defects in oligodendroglia cause myelination deficits and behavioral abnormalities in Huntington disease. Proc. Natl. Acad. Sci. USA 116, 9622–9627 (2019).
Gangwani, M. R. et al. Neuronal and astrocytic contributions to Huntington’s disease dissected with zinc finger protein transcriptional repressors. Cell Rep. 42, 111953 (2023).
Al-Dalahmah, O. et al. Single-nucleus RNA-seq identifies Huntington disease astrocyte states. Acta Neuropathol. Commun. 8, 19 (2020).
Diaz-Castro, B., Gangwani, M. R., Yu, X., Coppola, G. & Khakh, B. S. Astrocyte molecular signatures in Huntington’s disease. Sci. Transl. Med. 11, eaaw8546 (2019).
Träger, U. et al. HTT-lowering reverses Huntington’s disease immune dysfunction caused by NFκB pathway dysregulation. Brain 137, 819–833 (2014).
Träger, U. et al. Characterisation of immune cell function in fragment and full-length Huntington’s disease mouse models. Neurobiol. Dis. 73, 388–398 (2015).
Pido-Lopez, J. et al. In vivo neutralization of the protagonist role of macrophages during the chronic inflammatory stage of Huntington’s disease. Sci. Rep. 8, 11447 (2018).
von Essen, M. R. et al. Early intrathecal T Helper 17.1 cell activity in Huntington disease. Ann. Neurol. 87, 246–255 (2020).
Arnaoutoglou, N. A., O’Brien, J. T. & Underwood, B. R. Dementia with Lewy bodies - from scientific knowledge to clinical insights. Nat. Rev. Neurol. 15, 103–112 (2019).
Howlett, D. R. et al. Regional multiple pathology scores are associated with cognitive decline in lewy body dementias. Brain Pathol. 25, 401–408 (2015).
Hansen, D., Ling, H., Lashley, T., Holton, J. L. & Warner, T. T. Review: Clinical, neuropathological and genetic features of Lewy body dementias. Neuropathol. Appl. Neurobiol. 45, 635–654 (2019).
Agrawal, S. et al. Association of traumatic brain injury with and without loss of consciousness with neuropathologic outcomes in community-dwelling older persons. JAMA Netw. Open 5, e229311 (2022).
Barnes, D. E. et al. Association of mild traumatic brain injury with and without loss of consciousness with dementia in US military veterans. JAMA Neurol. 75, 1055–1061 (2018).
Mackenzie, I. R. Activated microglia in dementia with Lewy bodies. Neurology 55, 132–134 (2000).
Imamura, K. et al. Cytokine production of activated microglia and decrease in neurotrophic factors of neurons in the hippocampus of Lewy body disease brains. Acta Neuropathol. 109, 141–150 (2005).
Iannaccone, S. et al. In vivo microglia activation in very early dementia with Lewy bodies, comparison with Parkinson’s disease. Parkinsonism Relat. Disord. 19, 47–52 (2013).
Surendranathan, A. et al. Early microglial activation and peripheral inflammation in dementia with Lewy bodies. Brain 141, 3415–3427 (2018).
Iba, M. et al. Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models. J. Neuroinflammation 17, 214 (2020).
Berzins, S. P. & Ritchie, D. S. Natural killer T cells: drivers or passengers in preventing human disease? Nat. Rev. Immunol. 14, 640–646 (2014).
Prasit, K. K. et al. Intratumoural administration of an NKT cell agonist with CpG promotes NKT cell infiltration associated with an enhanced antitumour response and abscopal effect. Oncoimmunology 11, 2081009 (2022).
Gate, D. et al. CD4(+) T cells contribute to neurodegeneration in Lewy body dementia. Science 374, 868–874 (2021).
Lin, Y. N. et al. Impaired CXCL12 signaling contributes to resistance of pancreatic cancer subpopulations to T cell-mediated cytotoxicity. Oncoimmunology 11, 2027136 (2022).
Grossman, M. et al. Frontotemporal lobar degeneration. Nat. Rev. Dis. Prim. 9, 40 (2023).
DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).
Hutton, M. et al. Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998).
Baker, M. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–919 (2006).
Guerreiro, R. J. et al. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 70, 78–84 (2013).
Rosso, S. M. et al. Medical and environmental risk factors for sporadic frontotemporal dementia: a retrospective case-control study. J. Neurol. Neurosurg. Psychiatry 74, 1574–1576 (2003).
Miller, Z. A. et al. TDP-43 frontotemporal lobar degeneration and autoimmune disease. J. Neurol. Neurosurg. Psychiatry 84, 956–962 (2013).
Miller, Z. A. et al. Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts: Completing the picture. Neurol. Neuroimmunol. Neuroinflamm 3, e301 (2016).
Bevan-Jones, W. R. et al. Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum. Brain 143, 1010–1026 (2020).
Pascual, B. et al. Neuroinflammation is highest in areas of disease progression in semantic dementia. Brain 144, 1565–1575 (2021).
Malpetti, M. et al. In vivo PET imaging of neuroinflammation in familial frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry 92, 319–322 (2021).
Sjögren, M., Folkesson, S., Blennow, K. & Tarkowski, E. Increased intrathecal inflammatory activity in frontotemporal dementia: pathophysiological implications. J. Neurol. Neurosurg. Psychiatry 75, 1107–1111 (2004).
Lok, H. C. et al. Elevated GRO-α and IL-18 in serum and brain implicate the NLRP3 inflammasome in frontotemporal dementia. Sci. Rep. 13, 8942 (2023).
Chu, M. et al. Peripheral inflammation in behavioural variant frontotemporal dementia: associations with central degeneration and clinical measures. J. Neuroinflammation 20, 65 (2023).
Galimberti, D. et al. Inflammatory molecules in Frontotemporal Dementia: cerebrospinal fluid signature of progranulin mutation carriers. Brain Behav. Immun. 49, 182–187 (2015).
Busse, M. et al. Alterations in the peripheral immune system in dementia. J. Alzheimers Dis. 58, 1303–1313 (2017).
Krabbe, G. et al. Microglial NFκB-TNFα hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia. Proc. Natl. Acad. Sci. USA 114, 5029–5034 (2017).
Ahmed, Z., Mackenzie, I. R., Hutton, M. L. & Dickson, D. W. Progranulin in frontotemporal lobar degeneration and neuroinflammation. J. Neuroinflammation 4, 7 (2007).
Zhang, J. et al. Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency. Nature 588, 459–465 (2020).
Wu, Y. et al. Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD. Cell Rep. 36, 109581 (2021).
Kleinberger, G. et al. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 36, 1837–1853 (2017).
Gerrits, E. et al. Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA sequencing of human cerebral cortex. Nat. Neurosci. 25, 1034–1048 (2022).
Marsan, E. et al. Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations. J. Clin. Invest 133, e164919 (2023).
Adamopoulos, I. E. & Kuchroo, V. IL-17A and IL-17F in tissue homeostasis, inflammation and regeneration. Nat. Rev. Rheumatol. 19, 535–536 (2023).
Sonnenberg, G. F. & Hepworth, M. R. Functional interactions between innate lymphoid cells and adaptive immunity. Nat. Rev. Immunol. 19, 599–613 (2019).
Lanier, L. L. Shades of grey-the blurring view of innate and adaptive immunity. Nat. Rev. Immunol. 13, 73–74 (2013).
Qi, H., Kastenmüller, W. & Germain, R. N. Spatiotemporal basis of innate and adaptive immunity in secondary lymphoid tissue. Annu. Rev. Cell Dev. Biol. 30, 141–167 (2014).
Pancer, Z. & Cooper, M. D. The evolution of adaptive immunity. Annu. Rev. Immunol. 24, 497–518 (2006).
Bekkering, S., Domínguez-Andrés, J., Joosten, L. A. B., Riksen, N. P. & Netea, M. G. Trained immunity: reprogramming innate immunity in health and disease. Annu. Rev. Immunol. 39, 667–693 (2021).
Farber, D. L., Netea, M. G., Radbruch, A., Rajewsky, K. & Zinkernagel, R. M. Immunological memory: lessons from the past and a look to the future. Nat. Rev. Immunol. 16, 124–128 (2016).
Pollard, A. J. & Bijker, E. M. A guide to vaccinology: from basic principles to new developments. Nat. Rev. Immunol. 21, 83–100 (2021).
Baccala, R. et al. Sensors of the innate immune system: their mode of action. Nat. Rev. Rheumatol. 5, 448–456 (2009).
Martinet, L. & Smyth, M. J. Balancing natural killer cell activation through paired receptors. Nat. Rev. Immunol. 15, 243–254 (2015).
López-Soto, A., Gonzalez, S., Smyth, M. J. & Galluzzi, L. Control of metastasis by NK cells. Cancer Cell 32, 135–154 (2017).
Johanson, T. M., Chan, W. F., Keenan, C. R. & Allan, R. S. Genome organization in immune cells: unique challenges. Nat. Rev. Immunol. 19, 448–456 (2019).
ElTanbouly, M. A. & Noelle, R. J. Rethinking peripheral T cell tolerance: checkpoints across a T cell’s journey. Nat. Rev. Immunol. 21, 257–267 (2021).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Galluzzi, L., Chan, T. A., Kroemer, G., Wolchok, J. D. & López-Soto, A. The hallmarks of successful anticancer immunotherapy. Sci. Transl. Med. 10, eaat7807 (2018).
Dersh, D., Hollý, J. & Yewdell, J. W. A few good peptides: MHC class I-based cancer immunosurveillance and immunoevasion. Nat. Rev. Immunol. 21, 116–128 (2021).
Korman, A. J., Garrett-Thomson, S. C. & Lonberg, N. The foundations of immune checkpoint blockade and the ipilimumab approval decennial. Nat. Rev. Drug Discov. 21, 509–528 (2022).
Galluzzi, L. et al. Classification of current anticancer immunotherapies. Oncotarget 5, 12472–12508 (2014).
Galluzzi, L., Humeau, J., Buqué, A., Zitvogel, L. & Kroemer, G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat. Rev. Clin. Oncol. 17, 725–741 (2020).
Petroni, G., Buque, A., Zitvogel, L., Kroemer, G. & Galluzzi, L. Immunomodulation by targeted anticancer agents. Cancer Cell 39, 310–345 (2021).
Petroni, G., Buqué, A., Coussens, L. M. & Galluzzi, L. Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment. Nat. Rev. Drug Discov. 21, 440–462 (2022).
Rodriguez-Ruiz, M. E., Vitale, I., Harrington, K. J., Melero, I. & Galluzzi, L. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment. Nat. Immunol. 21, 120–134 (2020).
Yamazaki, T. et al. Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy. Nat. Immunol. 21, 1160–1171 (2020).
Acknowledgements
Mireia Niso-Santano is supported by MCIN/AEI/10.13039/501100011033/ and “ERDF A way of making Europe” (PID2022-138854OB-I00), as well as by MCIN/AEI /10.13039/501100011033 and “European Union NextGenerationEU/PRTR” (CNS2022-135801). L.G. is/has been supported (as a principal investigator (PI) unless otherwise indicated) by one NIH R01 grant (CA271915), two Breakthrough Level 2 grants from the US DoD BCRP (BC180476P1, BC210945), a grant from the STARR Cancer Consortium (I16-0064), a Transformative Breast Cancer Consortium Grant from the US DoD BCRP (W81XWH2120034, PI: Silvia C. Formenti), a U54 grant from NIH/NCI (CA274291, PI: Joseph Deasy, Silvia C. Formenti, Ralph Weichselbaum), the 2019 Laura Ziskin Prize in Translational Research (ZP-6177, PI: Silvia C. Formenti) from the Stand Up to Cancer (SU2C), a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Selina Chen-Kiang) grant from the Leukemia and Lymphoma Society (LLS), a Rapid Response Grant from the Functional Genomics Initiative (New York, US), by a pre-SPORE grant (PI: Sandra Demaria, Silvia C. Formenti), a Collaborative Research Initiative Grant and a Clinical Trials Innovation Grant from the Sandra and Edward Meyer Cancer Center (New York, US), startup funds from the Dept. of Radiation Oncology at Weill Cornell Medicine (New York, US), industrial collaborations with Lytix Biopharma (Oslo, Norway), Promontory (New York, US) and Onxeo (Paris, France), as well as donations from Promontory (New York, US), the Luke Heller TECPR2 Foundation (Boston, US), Sotio a.s. (Prague, Czech Republic), Lytix Biopharma (Oslo, Norway), Onxeo (Paris, France), Ricerchiamo (Brescia, Italy), and Noxopharm (Chatswood, Australia).
Author information
Authors and Affiliations
Contributions
M.N.S. and L.G. conceived the article. M.N.S. and L.G. wrote the first version of the manuscript and designed display items with constructive input from J.M.F. All authors approve the submitted version of the article.
Corresponding authors
Ethics declarations
Conflict of interest
L.G. is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation, and holds Promontory stock options. All other authors have no conflicts to declare.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Niso-Santano, M., Fuentes, J.M. & Galluzzi, L. Immunological aspects of central neurodegeneration. Cell Discov 10, 41 (2024). https://doi.org/10.1038/s41421-024-00666-z
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41421-024-00666-z