Table 1 Evidence of the involvement of TLRs in PD through different studies
From: The role of Toll-like receptors and neuroinflammation in Parkinson’s disease
Study design | Type of evidence | Year | Most pronounced result | Conclusion | References |
|---|---|---|---|---|---|
Comparing two genetic variants of TLR2 in the Han Chinese population | Clinical | 2017 | The variant allele T of the rs3804099 was higher in sporadic PD cases than rs3804100 allele | Single nucleotide polymorphism of TLR2 is associated with the development of sporadic PD in the Han Chinese population | [83] |
Comparing the blood cells of PD patients and control group in response to TLR3 or TLR7,8 agonists | Clinical | 2016 | Patient blood cells produced lower cytokine levels after administration of TLR2 and TLR7/8 compared to the control group | Blood leukocyte TLR2 and TLR7/8 are impaired in PD, whose association with PD brain damages should be investigated in future studies | [149] |
Using flow cytometry and western blot to find TLR2 and TLR4 expression in blood and brain of PD patients | Clinical | 2014 | Increased expression of TLR2 and TLR4 in circulating monocytes, and increased TLR4 in B cells and caudate and putamen brain regions in PD patients | TLR2 and TLR4 are modulated in the blood and brain of PD patients | [150] |
Examining the expression of TLR2 in postmortem brain tissue from PD patients and matched controls | Clinical | 2017 | TLR2 is increased in PD brain its level correlates with the α-synuclein accumulation, the neuronal TLR2 expression (but not glial expression) was associated with PD staging | The increased expression of TLR2 on neurons might serve as a target for PD therapy | [151] |
Comparing the phenotype and TLR2 expression between PD patients and incidental Lewy body disease (iLBD) cases and control group | Clinical | 2014 | Pronounced increase of microglial TLR2 expression in iLBD cases (but not PD cases) compared to control, Increase in amoeboid microglia in PD cases | TLR2 may play a significant role in microglia-mediated responses in PD | [152] |
In vitro study, comparing the response of murine TLR4-knockdown microglia and wild-type microglia to Paraquat | Clinical | 2020 | Paraquat-induced production of inflammatory cytokines was significantly reduced in TLR4-knockdown microglia | TLR4 contributes to neuroinflammation in the Paraquat-induced model of neurodegeneration | [153] |
Comparing postmortem brains of PD dementia (PDD) and PD with no dementia (PDND) patients and control group | Clinical | 2020 | Upregulation of TLR4 in the substantia nigra, frontal cortex, and amygdala in both PDD and PDND patients compared to control group | TLR4 contributes to neuroinflammation in PD | [97] |
Comparing the colonic biopsy samples of PD patients and control group | Clinical | 2019 | Higher expression of the endotoxin-specific ligand TLR4, CD3 + T cells, and cytokine expression, and dysbiosis in colonic samples of PD patients | TLR4 contributes to neuroinflammation and intestine inflammation in PD | [98] |
Using flow cytometry and western blot to find TLR2 and TLR4 expression in blood and brain of PD patients | Clinical | 2014 | Increased expression of TLR2 and TLR4 in circulating monocytes, and increased TLR4 in B cells and caudate and putamen brain regions in PD patients | TLR2 and TLR4 are modulated in the blood and brain of PD patients | [150] |
Comparing single nucleotide polymorphisms of TLR9 between PD patients and control group | Clinical | 2020 | The DNA analysis of samples showed that rs352140 T allele of TLR9 was associated with reduced risk of PD | TLR9 SNPs are associated with PD risk | [154] |
Comparing the WT and TLR4-deficient MPTP-induced mice brain regions by Fourier Transform Infrared | Animal/in vitro | 2017 | WT mice were more prone to dopaminergic neuron degeneration following MPTP | TLR4 play roles in biochemical changes relating to neurodegeneration in MPTP-induced animal model of PD | [100] |
In vivo model of PD using MPTP mice | Animal/in vitro | 2019 | The absence of TLR4 prevented inflammation, cytokine production, dopamine depletion, modulated inflammasome pathway, and reduced astrogliosis, and α-synuclein-positive neurons | TLR4 may be an attractive therapeutic target for reversing PD-like manifestations in PD animal model | [155] |
Male rats were given intra-striatal injections of 6-hydroxydopamine, rotenone, LPS, or Poly I:C, and the expression of TLR3 and TLR4 were examined | Animal/in vitro | 2017 | Prominent changes in TLR3 and TLR4 expression in the inflamed striatum of all rats | TLR3 and TLR4 play significant roles in inducing PD-like symptoms in 6OHDP-induced animal model of PD | [102] |
Comparing the behavior and biochemistry of striatal and SN brain regions of MPTP-induced wild-type mice and MPTP-induced TLR4-deficient mice | Animal/in vitro | 2019 | TLR4 deficiency significantly improved MPTP-induced motor deficits, attenuated α-synuclein reduction, and improved neuroinflammation | TLR4 contributes significantly to PD-like symptoms in MPTP-induced animal model of PD | [156] |
Comparing α-synuclein-treated TLR2 knockout mice and WT mice microglia | Animal/in vitro | 2013 | Extracellular oligomeric α-synuclein released from neuron cells serve as a ligand for TLR2 and initiate an inflammatory response | TLR2 and oligomeric α-synuclein both might have the potential to serve as novel therapeutic targets in PD | [157] |
Comparing TLR2 knockout and WT mice | Animal/in vitro | 2016 | Neuron-derived α-synuclein activates TLR2 and leads to neuroinflammation-induced neurodegeneration | TLR2 is an essential molecule mediating non-cell-autonomous neurotoxic effects of α-synuclein in the genetic animal model of PD | [158] |
Comparing A53T + TLR2 + / + and A53T + TLR2 knockout mice | Animal/in vitro | 2016 | Inactivating TLR2 led to phagocytosis activation and decreased α-synuclein aggregation Moreover, activation of TLR2 led to reduced phagocytosis activity by regulating AKT/mTOR | TLR2 plays a significant role in the phagocytosis activities of microglia | [90] |