Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets

In the paper

“Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity.”

• Also stated in: § Introduction · plain

  “Recent advances in scRNA-seq and snRNA-seq technologies have identified high spatial and temporal heterogeneity levels and unique disease-related signatures of these reactive microglia without correspondence to the canonical M1/M2 classification in neurodegenerative diseases.”

What the sources say

• Partly supported

  The Results describe distinct disease-associated microglial states and a transition from homeostatic microglia as Alzheimer’s disease progresses; the Introduction locates these cells near amyloid plaques. This supports spatial and temporal differences in the studied disease models, but the cited passages do not establish high heterogeneity across neurodegenerative diseases or address correspondence with the M1/M2 classification. (LLM, conf=0.82)

  cites [13] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e1217 (2017). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results identify distinct microglial states in a single-cell dataset from an Alzheimer’s mouse model, and the Discussion reports expression differences between cerebellar and cortical microglia and between aged and young mice. These passages support heterogeneity across cells, regions, and ages, but do not establish that single-cell technologies revealed high spatial and temporal heterogeneity of reactive microglia across neurodegenerative diseases. The copy also does not directly compare those states with the M1/M2 classification. (LLM, conf=0.84)

  cites [14] Friedman, B. A. et al. Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer’s disease not evident in mouse models. Cell Rep. 22, 832–847 (2018). sourceExperimental — accuracy not yet measured
• Not checked yetcites [15] Gerrits, E. et al. Distinct amyloid-beta and tau-associated microglia profiles in Alzheimer’s disease. Acta Neuropathol. 141, 681–696 (2021). source

In the paper

“Notably, DAMs were localized near Aβ plaques and participated in the clearance of β-amyloid.”

What the sources say

• Supported

  The Results (page unavailable) place DAM-marker-positive microglia near Aβ plaques and report intracellular Aβ particles in those cells. The authors conclude that DAM actively participate in dismantling and digesting amyloid plaques, supporting the paraphrase about clearance. (LLM, conf=0.90)

  cites [13] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e1217 (2017). source

In the paper

“other studies found that TREM2 deficiency significantly reduced brain atrophy and prevented microglial activation in tau transgenic mice.”

What the sources say

• Partly supported

  The Results section, “TREM2 Deficiency in PS19 Mice Attenuates Tau-Mediated Neurodegeneration” (page unavailable), reports significantly less ventricular enlargement and reduced brain atrophy in TREM2-deficient tau-transgenic mice. The Results section, “Nine-Month-Old T2−/−PS Mice Have Decreased Microglial Activation” (page unavailable), reports reduced microglial activation, not that activation was prevented entirely. (LLM, conf=0.88)

  cites [178] 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). sourceExperimental — accuracy not yet measured
• Not checked yetcites [179] 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). source

In the paper

“Firstly, microglial activation colocalized and correlated with tau pathology in PSP patients374,378 and transgenic mice expressing mutant tau P301L.380”

What the sources say

• Not checked yetcites [374] Ishizawa, K. & Dickson, D. W. Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J. Neuropathol. Exp. Neurol. 60, 647–657 (2001). source
• Supported

  The Discussion reports a positive correlation between PET measures of microglial activation and tau pathology across brain regions in PSP patients and concludes that the two are macroscopically co-localized. The transgenic-mouse clause has a separate citation (380) and is not attributed to this source. (LLM, conf=0.93)

  cites [378] Malpetti, M. et al. Neuroinflammation and tau colocalize in vivo in progressive supranuclear palsy. Ann. Neurol. 88, 1194–1204 (2020). source
• Not checked yetcites [380] Sasaki, A. et al. Microglial activation in brain lesions with tau deposits: comparison of human tauopathies and tau transgenic mice TgTauP301L. Brain Res. 1214, 159–168 (2008). source

In the paper

“Microglial elimination in R6/2 mice prevented the loss of PNNs and dramatically increased PNNs in the brains of naïve littermates.”

What the sources say

• Supported

  The PNN results section (p. 17) reports that microglial elimination prevented disease-associated PNN loss in the somatosensory and motor cortices of R6/2 mice. It also reports a dramatic increase in PNN density across every examined brain region of naïve non-transgenic mice; the methods (p. 6) identify the non-transgenic mice as littermates. (LLM, conf=0.94)

  cites [456] 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). source

In the paper

“Microglia, the resident macrophages of the central nervous system (CNS), utilize their specific receptor repertoire to monitor the microenvironment dynamically in the brain.”

What the sources say

• Not checked yetcites [1] Arcuri, C., Mecca, C., Bianchi, R., Giambanco, I. & Donato, R. The pathophysiological role of microglia in dynamic surveillance, phagocytosis and structural remodeling of the developing CNS. Front. Mol. Neurosci. 10, 191 (2017). source

In the paper

“Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration.”

In the paper

“peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression.”

• Also stated in: § Conclusion · plain

  “Peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression.”

In the paper

“Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions.”

What the sources say

• Not checked yetcites [11] Savage, J. C., Carrier, M. & Tremblay, M. E. Morphology of microglia across contexts of health and disease. Methods Mol. Biol. 2034, 13–26 (2019). source
• Not checked yetcites [12] Bouvier, D. S. et al. High resolution dissection of reactive glial nets in Alzheimer’s disease. Sci. Rep. 6, 24544 (2016). source

In the paper

“play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration.”

In the paper

“However, microglia activation is more varied and dynamic than ever anticipated, both in -omics features and functional consequences, indicating that microglia respond differently in different diseases.”

In the paper

“Both intrinsic factors (species, sex, genetic background, etc.) and extrinsic factors (pathogens, nutrition, microbiota, etc.) influence microglial states.”

What the sources say

• Not checked yetcites [8] Paolicelli, R. C. et al. Microglia states and nomenclature: a field at its crossroads. Neuron 110, 3458–3483 (2022). source

In the paper

“Microglia activation was observed in various neurodegenerative diseases.”

In the paper

“Microglial cell colonization of the CNS is evolutionarily conserved across vertebrate species and occurs before the formation of the neuroectoderm-derived glial cell types such as oligodendrocytes and astrocytes.”

What the sources say

• Not checked yetcites [48] Verney, C., Monier, A., Fallet-Bianco, C. & Gressens, P. Early microglial colonization of the human forebrain and possible involvement in periventricular white-matter injury of preterm infants. J. Anat. 217, 436–448 (2010). source
• Not checked yetcites [49] Schlegelmilch, T., Henke, K. & Peri, F. Microglia in the developing brain: from immunity to behaviour. Curr. Opin. Neurobiol. 21, 5–10 (2011). source

In the paper

“Thus, primary EMPs, secondary EMP-derived fetal liver monocytes, and HSC-derived fetal liver monocytes contribute to all tissue macrophages, with microglia arising solely from primary EMP.”

What the sources say

• Not checked yetcites [41] Li, Q. & Barres, B. A. Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 18, 225–242 (2018). source

In the paper

“Once A1 astrocytes are induced, they lose their essential functions such as supporting neuronal survival, and they also promote neuroinflammation, which contributes to the progression of neurodegenerative diseases.”

What the sources say

• Not checked yetcites [113] 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). source

In the paper

“Microglia communicate with nearly all cell types in the brain to facilitate developmental process, maintain homeostasis, assist in tissue repair, and contribute to the pathogenesis of diseases.”

What the sources say

• Not checked yetcites [53] 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). source
• Not checked yetcites [97] Frost, J. L. & Schafer, D. P. Microglia: architects of the developing nervous system. Trends Cell Biol. 26, 587–597 (2016). source

In the paper

“Microglia phagocytose misfolded proteins, cellular debris, and dying cells to maintain homeostasis.”

What the sources say

• Not checked yetcites [2] Sarlus, H. & Heneka, M. T. Microglia in Alzheimer’s disease. J. Clin. Invest. 127, 3240–3249 (2017). source

In the paper

“The primary pathological features of AD are extraneuronal amyloid plaques formed by the deposition of Aβ peptide in the brain and intracellular neurofibrillary tangles (NFTs) caused by abnormal aggregation of tau protein.”

What the sources say

• Not checked yetcites [122] Duyckaerts, C., Delatour, B. & Potier, M. C. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 118, 5–36 (2009). source

In the paper

“TREM2 is expressed highly and exclusively in microglia in the brain.”

What the sources say

• Not checked yetcites [162] Jay, T. R., von Saucken, V. E. & Landreth, G. E. TREM2 in neurodegenerative diseases. Mol. Neurodegener. 12, 56 (2017). source

In the paper

“In a humanized APP mouse model, MGnD microglia, a class of disease-reactive microglia common in neurodegeneration, hypersecrete EVs containing phosphorylated tau (pTau), accelerating tau propagation.”

What the sources say

• Not checked yetcites [160] Clayton, K. et al. Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model. Mol. Neurodegener. 16, 18 (2021). source

In the paper

“Keren-Shaul et al.13 first identified a subgroup of microglia in AD, termed disease-associated microglia (DAM), which participated in the clearance of Aβ. DAMs were localized near Aβ plaques”

What the sources say

• Not checked yetcites [13] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e1217 (2017). source

In the paper

“TREM2 has been reported to promote the conversion of microglia to the DAM phenotype, which is responsible for Aβ phagocytosis.”

What the sources say

• Not checked yetcites [13] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e1217 (2017). source

In the paper

“LC3-associated endocytosis (LANDO) in microglia facilitates Aβ receptor recycling, increasing Aβ surface receptors, thus promoting Aβ clearance”

What the sources say

• Not checked yetcites [146] Heckmann, B. L. et al. LC3-associated endocytosis facilitates beta-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s disease. Cell 178, 536–551.e514 (2019). source

In the paper

“However, when these growing pathological deposits chronically stimulate microglia, the protective microglia may convert to dysfunctional microglia, aggravating the disease progression of AD.”

In the paper

“Aβ binds to microglial TREM2, which activates TREM2 signaling and lead to the enhanced phagocytosis of microglia.”

What the sources say

• Not checked yetcites [174] Hammond, T. R., Marsh, S. E. & Stevens, B. Immune signaling in neurodegeneration. Immunity 50, 955–974 (2019). source

In the paper

“BACE-1 inhibition in microglia facilitated the microglia phenotype transition from homeostatic to stage 1 disease-associated microglia (DAM-1) signature148 and thus enhanced amyloid clearance and improved cognitive performance in AD mice.”

What the sources say

• Not checked yetcites [148] Singh, N. et al. BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1. Sci. Adv. 8, eabo1286 (2022). source
• Not checked yetcites [149] Singh, N., Das, B., Zhou, J., Hu, X. & Yan, R. Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance. Sci. Adv. 8, eabo3610 (2022). source

In the paper

“In contrast, NgR-deficient AD mice reduced amyloid burden and improved cognitive impairment.”

What the sources say

• Not checked yetcites [147] Wang, J. et al. Nogo receptor impairs the clearance of fibril amyloid-beta by microglia and accelerates Alzheimer’s-like disease progression. Aging Cell 20, e13515 (2021). source

In the paper

“After being released from microglia, ASC specks bind to and promote the cross-seeding of Aβ, leading to amyloid seeding and spreading of amyloid pathology.”

What the sources say

• Not checked yetcites [153] Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer’s disease. Nature 552, 355–361 (2017). source

In the paper

“Loss of TREM2 function impaired Aβ phagocytosis by microglia and increased amyloid seeding in AD mouse models.”

What the sources say

• Not checked yetcites [169] Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015). source
• Not checked yetcites [170] Parhizkar, S. et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat. Neurosci. 22, 191–204 (2019). source

In the paper

“Compared with APOE4, APOE3 lipoproteins induce faster microglial migration towards Aβ, facilitate Aβ uptake, and ameliorate cognition.”

What the sources say

• Not checked yetcites [151] Fitz, N. F. et al. Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease. Nat. Commun. 12, 3416 (2021). source

In the paper

“enhancing TREM2 signaling by TREM2 agonist antibody, direct delivery of the TREM2 gene, or stimulating other pathways to increase TREM2 expression in the brains of AD mice enhanced Aβ phagocytosis and improved cognitive behaviors.”

What the sources say

• Not checked yetcites [171] Schlepckow, K. et al. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol. Med. 12, e11227 (2020). source
• Not checked yetcites [172] 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). source
• Not checked yetcites [173] Zhao, P. et al. A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer’s disease. Sci. Transl. Med. 14, eabq0095 (2022). source

In the paper

“AD1-microglia were localized near Aβ plaques and were strongly correlated with the tissue Aβ load.”

In the paper

“Microglial autophagy deficiency can lead to dysregulation of lipid metabolism, induce microglia into a pro-inflammatory state, and as a result, enhance intraneuronal tau pathology and its spreading.”

What the sources say

• Not checked yetcites [158] Xu, Y., Propson, N. E., Du, S., Xiong, W. & Zheng, H. Autophagy deficiency modulates microglial lipid homeostasis and aggravates tau pathology and spreading. Proc. Natl Acad. Sci. USA 118, e2023418118 (2021). source

In the paper

“With aging, the Nogo receptor (NgR) expression on microglia increased, impairing microglial phagocytosis and clearance of Aβ.”

What the sources say

• Not checked yetcites [147] Wang, J. et al. Nogo receptor impairs the clearance of fibril amyloid-beta by microglia and accelerates Alzheimer’s-like disease progression. Aging Cell 20, e13515 (2021). source

In the paper

“In the early stage of the disease, this response may be protective. The reactive microglia migrate to the vicinity of pathological deposits such as Aβ or tau and then engulf and eliminate them.”

In the paper

“in contrast, LANDO-deficient AD mice induced neurodegeneration and memory deficits.”

What the sources say

• Not checked yetcites [146] Heckmann, B. L. et al. LC3-associated endocytosis facilitates beta-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s disease. Cell 178, 536–551.e514 (2019). source

In the paper

“the microglia in the midbrain had a decreased complexity compared to those in the striatum, showing that midbrain microglia had a muted reaction to an inflammatory stimulus, displaying a tolerogenic rather than primed phenotype.”

What the sources say

• Not checked yetcites [218] Uriarte Huarte, O. et al. Single-cell transcriptomics and in situ morphological analyses reveal microglia heterogeneity across the nigrostriatal pathway. Front. Immunol. 12, 639613 (2021). source

In the paper

“the researchers observed an increased number in reactive microglia and a reduction in oligodendrocyte numbers in PD patients.”

What the sources say

• Not checked yetcites [215] Smajic, S. et al. Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain 145, 964–978 (2022). source

In the paper

“The microglial activation trajectory extends from P2RY12high cells to two activation branches, one with highly expressed HSP90AA1 or IL1B241 cells and the other containing GPNMBhigh cells.”

What the sources say

• Not checked yetcites [215] Smajic, S. et al. Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain 145, 964–978 (2022). source

In the paper

“Peripheral inflammation can also affect the brain through the blood-brain barrier or the autonomic nervous system, triggering microglial activation and contributing to neurodegeneration.”

What the sources say

• Not checked yetcites [225] Ferrari, C. C. & Tarelli, R. Parkinson’s disease and systemic inflammation. Parkinsons Dis. 2011, 436813 (2011).

In the paper

“Responding to tau pathology, in the early stages of AD, TREM2 may suppress tau seeding, but later in AD, it may aggravate tau propagation.”

In the paper

“Fibrinogen leaked from the site of cerebrovascular damage into the brain and subsequently bound to the receptor CD11b on the surface of microglia. The interaction of fibrinogen and CD11b mediated microglial activation led to spine loss and promoted cognitive deficits in the 5×FAD mice.”

What the sources say

• Not checked yetcites [200] Merlini, M. et al. Fibrinogen induces microglia-mediated spine elimination and cognitive impairment in an Alzheimer’s disease model. Neuron 101, 1099–1108.e1096 (2019). source

In the paper

“A higher level of NLRP3 inflammasome has been observed in microglial cells in the SN of PD patients, which has been linked to the secretion of pro-inflammatory cytokines associated with neurodegeneration.”

What the sources say

• Not checked yetcites [223] Gordon, R. et al. Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice. Sci. Transl. Med. 10, eaah4066 (2018). source
• Not checked yetcites [224] Haque, M. E. et al. Targeting the microglial NLRP3 inflammasome and its role in Parkinson’s disease. Mov. Disord. 35, 20–33 (2020). source

In the paper

“Pathologically, PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) as well as the accumulation of misfolded α-syn in Lewy bodies.”

In the paper

“Overall, microglia are a double-edged sword in AD. Microglia phagocytose Aβ and tau, limit propagation of Aβ and tau pathology, and can also accelerate Aβ and tau spreading and lead to neurodegeneration.”

In the paper

“which supports the hypothesis that microglia and sTREM2 play a protective role in AD.”

In the paper

“Chronically depleting microglia before and during plaque development in two AD transgenic mouse models significantly reduced PNN loss, indicating that microglia promote plaque-dependent PNN loss.”

What the sources say

• Not checked yetcites [202] Crapser, J. D. et al. Microglia facilitate loss of perineuronal nets in the Alzheimer’s disease brain. EBioMedicine 58, 102919 (2020). source

In the paper

“the mutation p.H157Y located at the cleavage site of TREM2 extracellular domain significantly increased TREM2 shedding with elevated sTREM2 levels in the brain and serum but associated with increased AD risk.”

What the sources say

• Not checked yetcites [192] Schlepckow, K. et al. An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol. Med. 9, 1356–1365 (2017). source
• Not checked yetcites [193] Thornton, P. et al. TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant. EMBO Mol. Med. 9, 1366–1378 (2017). source

In the paper

“APP/PS1 mice treated with Trem2 knockdown antisense oligonucleotides (ASOs) through the ventricles at late stages exhibited a 50% reduction in plaque load. In contrast, administration of ASOs at early stages did not affect plaque load.”

What the sources say

• Not checked yetcites [180] Schoch, K. M. et al. Acute Trem2 reduction triggers increased microglial phagocytosis, slowing amyloid deposition in mice. Proc. Natl Acad. Sci. USA 118, e2100356118 (2021). source

In the paper

“Notably, microglial activation was discovered not only in individuals with long-term illnesses but also in patients who were just diagnosed.”

What the sources say

• Not checked yetcites [214] 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). source

In the paper

“In 1988, reactive microglia were first observed in the substantia nigra (SN) of postmortem brain tissue from PD patients.”

What the sources say

• Not checked yetcites [210] 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). source

In the paper

“Microglial activation begins early and persists throughout the course of PD.”

What the sources say

• Not checked yetcites [209] Janda, E., Boi, L. & Carta, A. R. Microglial phagocytosis and its regulation: a therapeutic target in Parkinson’s disease? Front. Mol. Neurosci. 11, 144 (2018). source

In the paper

“In the 5×FAD mouse model and human cortical tissue, extensive loss of PNNs has been observed, and the loss of PNNs was proportional to plaque burden.”

What the sources say

• Not checked yetcites [202] Crapser, J. D. et al. Microglia facilitate loss of perineuronal nets in the Alzheimer’s disease brain. EBioMedicine 58, 102919 (2020). source

In the paper

“The above studies indicated that dysfunctional microglia in AD promoted the clearance of synapses and PNNs and impaired neuronal plasticity and activity”

In the paper

“experimental evidence revealed that sTREM2 directly bound to neurons in mouse models of AD194 and inhibited LTP induction.”

What the sources say

• Not checked yetcites [194] Song, W. M. et al. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med. 215, 745–760 (2018). source
• Not checked yetcites [195] Moutinho, M. et al. TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation. Genome Med. 15, 11 (2023). source

In the paper

“Using scRNA-seq and immunofluorescence analyses in a murine model, the researchers identified a distinct subset of microglia in the midbrain that displayed an intrinsic transcriptional immune alerted signature. Notably, some genes, including Casp4, Ccl4, Cd83, and H2-ab1, were exclusively overexpressed in the immune alerted subset. Interestingly, this subset was absent in other brain regions, such”

What the sources say

• Not checked yetcites [218] Uriarte Huarte, O. et al. Single-cell transcriptomics and in situ morphological analyses reveal microglia heterogeneity across the nigrostriatal pathway. Front. Immunol. 12, 639613 (2021). source

In the paper

“Extracellular α-syn exposure increases pro-inflammatory cytokine production in microglial cells.”

In the paper

“Studies have suggested that the CX3CL1-CX3CR1 signaling pathway is essential for maintaining a healthy balance in microglial activity, regulating chemoattraction and synaptic plasticity, and reducing microglia-mediated inflammation and neurotoxicity.”

What the sources say

• Not checked yetcites [252] Pabon, M. M., Bachstetter, A. D., Hudson, C. E., Gemma, C. & Bickford, P. C. CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson’s disease. J. Neuroinflammation 8, 9 (2011). source

In the paper

“Compared to healthy controls, PD patients had increased frequencies of Th1 cells and higher levels of IL10 and IL17A in their serum.”

In the paper

“Another protein that regulates microglial activation is CD200, which is expressed on the surface of neurons and interacts with microglial CD200R. Dysregulation of the CD200-CD200R pathway has been linked to increased microglial activation and degeneration of dopaminergic neurons.”

What the sources say

• Not checked yetcites [253] Zhang, S. et al. CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson’s disease. J. Neuroinflammation 8, 154 (2011). source

In the paper

“Additionally, LPS/IFN-γ induces microglial activation, increases exosome release,235 and microglia-derived exosomes facilitate the transmission of α-syn to neurons, accelerating neuronal death.”

What the sources say

• Not checked yetcites [235] Tsutsumi, R. et al. Involvement of exosomes in dopaminergic neurodegeneration by microglial activation in midbrain slice cultures. Biochem. Biophys. Res. Commun. 511, 427–433 (2019). source
• Not checked yetcites [236] George, S. et al. Microglia affect alpha-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease. Mol. Neurodegener. 14, 34 (2019). source

In the paper

“Production of neuroinflammation may trigger α-syn oligomerization, leading to a harmful cycle of microglial activation.”

What the sources say

• Not checked yetcites [237] Allen Reish, H. E. & Standaert, D. G. Role of alpha-synuclein in inducing innate and adaptive immunity in Parkinson disease. J. Parkinsons Dis. 5, 1–19 (2015). source

In the paper

“Previous studies have shown that LRRK2 expression is particularly high in various immune cells, including microglia, macrophages, and monocytes. In contrast, its expression in T cells is relatively low.258,259”

What the sources say

• Not checked yetcites [258] Thevenet, J., Pescini Gobert, R., Hooft van Huijsduijnen, R., Wiessner, C. & Sagot, Y. J. Regulation of LRRK2 expression points to a functional role in human monocyte maturation. PLoS ONE 6, e21519 (2011). source
• Not checked yetcites [259] Moehle, M. S. et al. LRRK2 inhibition attenuates microglial inflammatory responses. J. Neurosci. 32, 1602–1611 (2012). source

In the paper

“Several animal models of PD show that microglial CB2 receptor activation is neuroprotective and improves motor symptoms.”

What the sources say

• Not checked yetcites [254] Price, D. A. et al. WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Eur. J. Neurosci. 29, 2177–2186 (2009). source
• Not checked yetcites [255] Chung, Y. C. et al. CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson’s disease. Exp. Mol. Med. 48, e205 (2016). source

In the paper

“Studies in PD mouse models and patients have shown upregulation and activation of CCR2, suggesting a detrimental role of infiltrating monocytes in PD.”

What the sources say

• Not checked yetcites [230] Hall, S. et al. Cerebrospinal fluid concentrations of inflammatory markers in Parkinson’s disease and atypical parkinsonian disorders. Sci. Rep. 8, 13276 (2018). source

In the paper

“Extracellular α-syn is taken up by microglia, perhaps via the autophagy receptor p62, and degraded by selective autophagy.”

What the sources say

• Not checked yetcites [239] Choi, I. et al. Microglia clear neuron-released alpha-synuclein via selective autophagy and prevent neurodegeneration. Nat. Commun. 11, 1386 (2020). source

In the paper

“The phagocytic ability of microglia is crucial for α-syn clearance and thus plays a role in the development of PD.”

What the sources say

• Not checked yetcites [241] Zhang, W. et al. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J. 19, 533–542 (2005). source

In the paper

“The researchers identified microglia-specific chromatin regions that regulated LRRK2 expression and showed that a specific regulatory DNA element containing the PD-associated genetic variant rs6581593 modulates LRRK2 expression in microglia.”

What the sources say

• Not checked yetcites [261] Langston, R. G. et al. Association of a common genetic variant with Parkinson’s disease is mediated by microglia. Sci. Transl. Med. 14, eabp8869 (2022). source

In the paper

“As CNS monitors, microglia take up and degrade α-syn, whose internalization can activate microglia and cause neuroinflammation.”

What the sources say

• Not checked yetcites [238] Grozdanov, V. & Danzer, K. M. Release and uptake of pathologic alpha-synuclein. Cell Tissue Res. 373, 175–182 (2018). source
• Not checked yetcites [239] Choi, I. et al. Microglia clear neuron-released alpha-synuclein via selective autophagy and prevent neurodegeneration. Nat. Commun. 11, 1386 (2020). source

In the paper

“DJ-1 dysfunction is implicated in a small percentage (1–2%) of inherited forms of early-onset PD.256”

What the sources say

• Not checked yetcites [256] Blauwendraat, C., Nalls, M. A. & Singleton, A. B. The genetic architecture of Parkinson’s disease. Lancet Neurol. 19, 170–178 (2020). source

In the paper

“α-syn overexpression has been shown to drive microglia polarization towards a pro-inflammatory phenotype, resulting in increased production of inflammatory cytokines such as IL-1β, IL-6, and TNF-α, as well as enzymes such as COX-2 and iNOS, and the generation of free radicals.”

What the sources say

• Not checked yetcites [242] Ardah, M. T., Merghani, M. M. & Haque, M. E. Thymoquinone prevents neurodegeneration against MPTP in vivo and modulates alpha-synuclein aggregation in vitro. Neurochem. Int. 128, 115–126 (2019). source
• Not checked yetcites [243] Sarkar, S. et al. Molecular signatures of neuroinflammation induced by αSynuclein aggregates in microglial cells. Front. Immunol. 11, 33 (2020). source

In the paper

“Furthermore, inhibition of LRRK2 kinase activity can lead to the phosphorylation of NF-κB inhibitory subunit p50 at the protein kinase A (PKA) -specific phosphorylation site S337. This results in an abnormally higher proportion of nuclear P-p50, which may inhibit the function of NF-κB, preventing efficient DNA binding and gene transcription activation in response to inflammation.262”

What the sources say

• Not checked yetcites [262] Russo, I. et al. Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-kappaB p50 signaling in cultured microglia cells. J. Neuroinflammation 12, 230 (2015). source

In the paper

“TLRs, including TLR2 and TLR4, are receptors expressed on microglia, which were demonstrated to play a role in the uptake of α-syn and the subsequent activation of microglia, boosting α-syn clearance by microglia.”

What the sources say

• Not checked yetcites [246] Fellner, L. et al. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360 (2013). source
• Not checked yetcites [247] Kim, C. et al. Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 4, 1562 (2013). source

In the paper

“Different conformation states of α-syn can activate microglia in PD, leading to increased secretion of IL-6, IL-1β, and NO.”

What the sources say

• Not checked yetcites [240] Calabresi, P. et al. Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis. 14, 176 (2023). source

In the paper

“α-syn-triggered phagocytic activity of microglia is critical for α-syn clearance and prevents accumulation of misfolded α-syn.”

In the paper

“Astrocytes convert MPTP into MPP+. Dopamine receptors in neurons take up MPP+, which inhibits the mitochondrial complex 1 of the electron transport chain, resulting in ATP depletion and oxidative stress. Ultimately, this leads to the death of dopaminergic cells and the activation of pro-inflammatory microglia.”

What the sources say

• Not checked yetcites [232] Tieu, K. A guide to neurotoxic animal models of Parkinson’s disease. Cold Spring Harb. Perspect. Med. 1, a009316 (2011). source

In the paper

“Several studies have revealed that the CX3CR1 receptor expressed on microglia is critical in neuron-microglia communication. This receptor specifically recognizes the protein CX3CL1.”

What the sources say

• Not checked yetcites [251] Harrison, J. K. et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl Acad. Sci. USA 95, 10896–10901 (1998). source

In the paper

“The α-syn-induced microglial activation depends on TLRs 1/2 signaling294 and TLR4 signaling.246”

What the sources say

• Not checked yetcites [294] Daniele, S. G. et al. Activation of MyD88-dependent TLR1/2 signaling by misfolded alpha-synuclein, a protein linked to neurodegenerative disorders. Sci. Signal 8, ra45 (2015). source
• Not checked yetcites [246] Fellner, L. et al. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360 (2013). source

In the paper

“The above evidence indicates that via a specific interaction with TLRs, the misfolded α-syn directly activates microglia and promotes the production and release of pro-inflammatory cytokines.”

What the sources say

• Not checked yetcites [294] Daniele, S. G. et al. Activation of MyD88-dependent TLR1/2 signaling by misfolded alpha-synuclein, a protein linked to neurodegenerative disorders. Sci. Signal 8, ra45 (2015). source
• Not checked yetcites [246] Fellner, L. et al. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360 (2013). source

In the paper

“In addition, microglia lacking DJ-1 showed increased mitochondrial activity, leading to elevated levels of ROS compared to normal microglia, and this effect was further increased by treatment with LPS.265”

What the sources say

• Not checked yetcites [265] Trudler, D., Weinreb, O., Mandel, S. A., Youdim, M. B. & Frenkel, D. DJ-1 deficiency triggers microglia sensitivity to dopamine toward a pro-inflammatory phenotype that is attenuated by rasagiline. J. Neurochem. 129, 434–447 (2014). source

In the paper

“Evidence consistently showed that microglia could phagocytize α-syn, but excessive uptake of α-syn by microglia led to neurodegeneration.”

What the sources say

• Not checked yetcites [295] Stefanova, N. et al. Toll-like receptor 4 promotes alpha-synuclein clearance and survival of nigral dopaminergic neurons. Am. J. Pathol. 179, 954–963 (2011). source

In the paper

“TLR4-mediated α-syn phagocytosis by microglia245,246,295 and induced NF-κB translocation, ROS production, and the release of pro-inflammatory cytokines such as TNF-α.246,296”

What the sources say

• Not checked yetcites [245] Venezia, S. et al. Toll-like receptor 4 stimulation with monophosphoryl lipid A ameliorates motor deficits and nigral neurodegeneration triggered by extraneuronal alpha-synucleinopathy. Mol. Neurodegener. 12, 52 (2017). source
• Not checked yetcites [246] Fellner, L. et al. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360 (2013). source
• Not checked yetcites [295] Stefanova, N. et al. Toll-like receptor 4 promotes alpha-synuclein clearance and survival of nigral dopaminergic neurons. Am. J. Pathol. 179, 954–963 (2011). source

In the paper

“In DJ-1 KO mice, microglia exhibited increased expression of phosphorylation levels of STAT1, as well as inflammatory mediators COX-2, iNOS, and TNF-α.264”

What the sources say

• Not checked yetcites [264] Kim, J. H. et al. DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: a novel anti-inflammatory function of DJ-1. Neurobiol. Dis. 60, 1–10 (2013). source

In the paper

“In contrast, TLR stimulation with a TLR4 selective agonist (monophosphoryl lipid A) in the same MSA mouse model ameliorated motor deficits and rescued nigral neurodegeneration.245”

What the sources say

• Not checked yetcites [245] Venezia, S. et al. Toll-like receptor 4 stimulation with monophosphoryl lipid A ameliorates motor deficits and nigral neurodegeneration triggered by extraneuronal alpha-synucleinopathy. Mol. Neurodegener. 12, 52 (2017). source

In the paper

“Mechanistic studies have found that α-syn aggregated in microglia led to a significant decrease in the phagocytic ability of microglia and triggered an inflammatory response, increasing the release of pro-inflammatory factors, ROS, and nitric oxide by microglia, which created a toxic environment eventually led to neurodegeneration295”

What the sources say

• Not checked yetcites [295] Stefanova, N. et al. Toll-like receptor 4 promotes alpha-synuclein clearance and survival of nigral dopaminergic neurons. Am. J. Pathol. 179, 954–963 (2011). source

In the paper

“Mechanismly, various factors including the abnormal accumulation of α-syn, microglial activation and neuroinflammation,276 autophagic impairment,277–279 mitochondrial,280 and proteasomal dysfunction281,282 are involved in the pathogenesis of MSA.”

What the sources say

• Not checked yetcites [276] Stefanova, N. et al. Microglial activation mediates neurodegeneration related to oligodendroglial alpha-synucleinopathy: implications for multiple system atrophy. Mov. Disord. 22, 2196–2203 (2007). source
• Not checked yetcites [277] Monzio Compagnoni, G. et al. Mitochondrial dysregulation and impaired autophagy in iPSC-derived dopaminergic neurons of multiple system atrophy. Stem Cell Rep. 11, 1185–1198 (2018). source
• Not checked yetcites [278] Schwarz, L., Goldbaum, O., Bergmann, M., Probst-Cousin, S. & Richter-Landsberg, C. Involvement of macroautophagy in multiple system atrophy and protein aggregate formation in oligodendrocytes. J. Mol. Neurosci. 47, 256–266 (2012). source
• Not checked yetcites [279] Tanji, K. et al. Alteration of autophagosomal proteins in the brain of multiple system atrophy. Neurobiol. Dis. 49, 190–198 (2013). source
• Not checked yetcites [280] Nakamoto, F. K. et al. The pathogenesis linked to coenzyme Q10 insufficiency in iPSC-derived neurons from patients with multiple-system atrophy. Sci. Rep. 8, 14215 (2018). source

In the paper

“Mutations in the SOD1 gene (encoding superoxide dismutase 1) occur in ~20% of cases,305”

What the sources say

• Not checked yetcites [305] Rosen, D. R. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 364, 362 (1993). source

In the paper

“Upregulated TLRs are a double-edged sword. It may have a protective effect by increasing the phagocytosis of α-syn by microglia, but as a result, it induces neuroinflammation and promotes neurodegeneration.”

In the paper

“Meanwhile, in the same MSA mouse model, the proportion of Th1 T cells and the level of INF-γ cytokine in the striatal tissue were significantly increased.301”

What the sources say

• Not checked yetcites [301] Williams, G. P. et al. T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease. Acta Neuropathol. 139, 855–874 (2020). source

In the paper

“Postmortem studies308–310 and in vivo PET studies311–313 revealed widespread cerebral microglial activation in patients with ALS,308–312 and even in pre-symptomatic ALS-related mutation carriers.309,313”

What the sources say

• Not checked yetcites [308] Henkel, J. S. et al. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann. Neurol. 55, 221–235 (2004). source
• Not checked yetcites [309] Brettschneider, J. et al. Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS ONE 7, e39216 (2012). source
• Not checked yetcites [310] Nolan, M. et al. Quantitative patterns of motor cortex proteinopathy across ALS genotypes. Acta Neuropathol. Commun. 8, 98 (2020). source
• Not checked yetcites [311] Turner, M. R. et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol. Dis. 15, 601–609 (2004). source
• Not checked yetcites [312] Zurcher, N. R. et al. Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: assessed with [(11)C]-PBR28. Neuroimage Clin. 7, 409–414 (2015). source
• Not checked yetcites [313] Tondo, G. et al. (11) C-PK11195 PET-based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis. Ann. Clin. Transl. Neurol. 7, 1513–1523 (2020). source

In the paper

“Mutation in C9orf72 accounts for 40% of familial ALS and FTD cases.303,304”

What the sources say

• Not checked yetcites [303] Renton, A. E., Chio, A. & Traynor, B. J. State of play in amyotrophic lateral sclerosis genetics. Nat. Neurosci. 17, 17–23 (2014). source
• Not checked yetcites [304] 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). source

In the paper

“Ninety-seven percent of patients with ALS and 50% of patients with FTD have cytoplasmic TDP-43 aggregates within neurons,332”

What the sources say

• Not checked yetcites [332] Irwin, D. J. et al. Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. Acta Neuropathol. 129, 469–491 (2015). source