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Review
. 2023 Sep 22;8(1):359.
doi: 10.1038/s41392-023-01588-0.

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets

Chao Gao #  1 , Jingwen Jiang #  1 , Yuyan Tan  2 , Shengdi Chen  3   4
Affiliations
Review

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets

Chao Gao et al. Signal Transduct Target Ther. .

Abstract

Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions. Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates and play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression. Microglia also act as a mobile vehicle to propagate protein aggregates. Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration. Thus, enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis and secretion, and promoting microglial conversion into a protective phenotype are considered to be promising strategies for the therapy of neurodegenerative diseases. Here we comprehensively review the biology of microglia and the roles of microglia in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and Huntington's disease. We also summarize the possible microglia-targeted interventions and treatments against neurodegenerative diseases with preclinical and clinical evidence in cell experiments, animal studies, and clinical trials.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Effect of microglia on Aβ and tau pathology in Alzheimer’s disease. Microglia phagocytose Aβ and tau, limit propagation of Aβ and tau pathology. Under pathological conditions, microglia could also accelerate Aβ and tau spreading and lead to neurodegeneration. a TREM2-dependent DAM limits tau seeding and spreading around plaques. b Reactive microglia drive tau spreading and toxicity by promoting neuroinflammation, such as activating NLRP3 inflammasome or inducing NF-kB signaling. Microglial autophagy deficiency leads to dysregulation of lipid metabolism, thus increasing intraneuronal tau pathology and its spreading. MGnD microglia, which is common in neurodegeneration, hypersecrete EVs containing pTau, accelerates tau propagation. c Microglia increase their expression of IL-3Rα after recognition of Aβ deposits. Astrocyte-derived IL-3 binds to the upregulated IL-3Rα in microglia, enhancing microglial migration toward Aβ deposits, and the clearance of Aβ aggregates. d TREM2 promotes the conversion of microglia to the DAM phenotype, and BACE-1 inhibition in microglia facilitates the microglia phenotype transition from homeostatic to DAM-1 signature. DAM and DAM-1 phenotypes enhance amyloid clearance. LC3-associated endocytosis (LANDO) in microglia facilitates Aβ receptor recycling, increases Aβ surface receptors, and thus promotes Aβ clearance. In contrast, the microglia with enhanced aerobic glycolysis, and NgR expression on microglia increased with aging inhibit the phagocytosis and clearance of Aβ. e Microglia facilitate Aβ spreading. Aβ induces immune system activation and the formation and release of ASC specks. After being released from microglia, ASC specks bind to and promote the cross-seeding of Aβ, leading to amyloid seeding and spreading. Created with https://BioRender.com
Fig. 2
Fig. 2
Dysfunctional microglia impair neuronal activity in Alzheimer’s disease. Dysfunctional microglia in AD promotes the clearance of synapses and PNNs and impairs neuronal plasticity and activity. a Microglia harboring an APOE4 allele shows altered cellular metabolism with increased intracellular and extracellular lipid accumulation. The extracellular lipid droplets directly decreased neuronal activity by increasing inward K+ currents. Microglia release Aβ-containing EVs and lead to synaptic dysfunction. Microglial phagocytosis of synapses is affected by astrocytes. Selective removal of astrocytic APOE4 decreases microglial phagocytosis of synaptic elements. b Fibrinogen leaks from the site of cerebrovascular damage into the brain and subsequently binds to the microglial surface receptor CD11b. The interaction of fibrinogen and CD11b mediates microglial activation and leads to spine loss. Microglia engulf perineuronal nets (PNN) and promote plaque-dependent PNN loss. Created with https://BioRender.com
Fig. 3
Fig. 3
α-syn resulting in microglial response in Parkinson’s disease. Microglia are activated by α-syn, which can be encountered through phagocytosis of synapses or exocytosis from neighboring neurons. Different forms of α-syn, including monomeric, oligomeric, and fibrillar, can be encountered as the disease progresses. The recognition, uptake, and phagocytosis of α-syn by microglia are dependent on the type of α-syn encountered and the involved receptors and proteins. α-syn has been shown to initiate a pro-inflammatory response by interacting with membrane receptors that activate NF-κB through various mediators and assemble the NLRP3 inflammasome, leading to the production of inflammatory mediators and free radicals. The CCL2-CCR2 axis is involved in the infiltration of monocytes into the inflamed brain. Upregulation and activation of CCR2 have been observed in PD mouse models and patients, indicating a potentially harmful role in infiltrating monocytes in PD. Local cytokine and tissue signals can then induce the transformation of monocytes to macrophages. These cascades also result in the proliferation and migration of microglia. Created with https://BioRender.com
Fig. 4
Fig. 4
Microglial roles in the pathogenesis of multiple system atrophy. a α-syn can interact with microglial toll-like receptors (TLRs) and then was phagocytosed by microglia in an MSA mouse model. But excessive uptake of α-syn by microglia led to a significant decrease in the phagocytic ability of microglia, triggered an inflammatory response of microglia including NF-κB and NLRP3 inflammasome signaling activation, reactive oxygen species production, pro-inflammatory cytokines upregulation, and eventually induced neurodegeneration. Besides, CD4 and CD8 T cell depletion attenuated α-syn-induced inflammation and demyelination in MSA mice. b Microglia act as a mobile vehicle to propagate α-syn after phagocytosis of α-syn in MSA patients. An in vitro study showed the ability of microglia to transport α-syn distally was impaired when treated with Epothilone D, a natural product that can inhibit microtubule activity. Created with https://BioRender.com
Fig. 5
Fig. 5
Microglial roles in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia. a TDP-43 could be released into the extracellular matrix via exosomes or cell death. TDP-43 interacted with microglial TREM2 and then increased their phagocytosis and clearance by microglia. Phagocytosis of TDP43 aggregates by microglia led to microglial activation, microglial NLRP3 inflammasome activation, and pro-inflammatory markers upregulation, which have neurotoxic effects on motor neurons. Besides, progranulin deficiency in microglia activated microglial NF-κB signaling and promoted the release of pro-inflammatory cytokines, leading to hyperexcitability of medium spiny neurons. b Homeostatic microglia are protective against ALS. Progranulin deficiency aggravated TDP-43 pathology, promoted synaptic pruning by microglia, and led to synaptic loss and neurodegeneration. Progranulin deficiency also led to microglial lysosomal dysfunction and reduced myelin debris degradation, leading to the accumulation of myelin debris in white matter. Besides, C9orf72 loss of function promoted microglial gene signature transition from a homeostatic to an inflammatory state and promoted synaptic pruning by microglia and synapse loss in neurons. c At the early stage of the ALS mouse model (SOD1 mice), the anti-inflammatory cytokine IL-10 was upregulated in microglia, and microglia presented with an anti-inflammatory phenotype, which was neuroprotective to motor neurons. But at the late stage, microglia presented with a pro-inflammatory phenotype, which was neurotoxic to motor neurons. d Peripheral nerve reactive macrophages along peripheral axons of motor neurons were activated in an ALS mouse model (SOD1 mutant mice). Replacing peripheral nerve macrophages at disease onset reduced microglial pro-inflammatory responses and prolonged survival in these mice. NK cell infiltration into the cerebral motor cortex and spinal cord was observed in an ALS mouse model (SOD1G93A). NK cell depletion induced a protective microglial phenotype and increased survival in these mice. Created with https://BioRender.com
Fig. 6
Fig. 6
Possible microglia-targeted interventions and treatments against neurodegenerative diseases. Proof-of-principle therapeutic strategies used in cell experiments, animal studies, and clinical trials are shown together. Regulation of neuroinflammation, inhibition of microglial exosome synthesis and secretion, altering microglial metabolism, altering the microglial phenotype, and TREM2 activation are potential therapeutic strategies in treating neurodegenerative diseases. Among these, modulating neuroinflammation is the most widely used therapeutic target
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