Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders
Abstract
:1. Introduction
2. TNF-α Receptor Signaling Pathways
2.1. TNF-α Receptor 1 Signaling
2.2. TNF-α Receptor 2 Signaling
3. TNF and Its Receptors—Involvement in Neurodegenerative Disorders
3.1. Alzheimer’s Disease
3.2. Parkinson’s Disease
3.3. Ischemic Stroke
3.4. Multiple Sclerosis
Condition | TNF-α family member | Tissue | Finding | Model | Ref. |
---|---|---|---|---|---|
Alzheimer’s disease (AD) | TNF-α | CNS | TNF-α protein levels are increased in AD brain tissue. | Human AD patients. | [86,87,88] |
Plasma and serum | TNF-α protein levels are increased in AD plasma and serum. | Human AD patients. | [83,84,85] | ||
TNFR1 and TNFR2 | CNS | TNFR1 protein levels are increased, TNFR2 protein levels are decreased. | Human AD patients. | [88,93] | |
Deletion of both TNFRs exacerbates AD pathology. | 3xTg-AD mouse model. | [96] | |||
Silencing or deletion of TNFR2 aggravates AD pathology. TNFR2 overexpression reverses these effects. | 3xTg-AD mouse model and APP23 mouse model. | [97] | |||
In vitro, TNFR2 silencing promotes Aβ neurotoxic effects. | SH-SY5Y cell line. | [100] | |||
Deletion of TNFR1 diminishes AD pathology. | 3xTg-AD mouse model and APP23 mouse model. | [91] | |||
sTNF-α inhibitors diminish AD pathology. | 3xTg-AD mouse model. | [99] | |||
sTNFR1 and sTNFR2 | CSF, serum and plasma | sTNFR1 levels are increased. sTNFR2 levels are unchanged or decreased. | Human control and MCI patients. | [159,160,161,162,163] | |
Higher sTNFR1 serum levels can predict conversion from MCI to AD. | Human control and MCI patients. | [161] | |||
sTNFR1 and sTNFR2 levels correlate with BACE1 activity and Aβ40 levels, as well as with tau CSF levels. | Human control and MCI patients. | [164] | |||
Parkinson’s disease (PD) | TNF-α | CNS and CSF | TNF-α levels are increased in brain and CSF. | Human control and PD patients. | [96,98] |
TNF-α levels are increased in brain. | α-Synuclein overexpression cell line and mouse models. | [106] | |||
TNFR1 | CNS | TNFR1 levels are increased in the substantia nigra. | Human control and PD patients. | [105] | |
sTNF-α inhibitors reduce cell death of dopamine neurons. | Rat 6-OHDA toxicity model. | [111,112,113,114] | |||
TNFR2 | CNS | Selective activation of TNFR2 protects dopaminergic neurons. | Neuronal culture, 6-OHDA toxicity model. | [110] | |
TNFR1 and TNFR2 | CNS | Deletion of both TNFRs protects from dopaminergic toxicity, while lack of either TNFRs alone is not protective. | Mouse, MPTP toxicity model. | [116] | |
sTNFR1 | Serum and plasma | Serum sTNFR1 levels are increased. | Human control and PD patients. | [102,104,165] | |
Higher serum sTNFR1 correlate with a later onset of sporadic PD. | Human control and PD patients. | [165] | |||
Elevated plasma sTNFR1 levels predict poorer executive functioning in PD. | Human control and PD patients. | [166] | |||
Ischemic stroke | TNF-α | CNS | TNF-α production is increased around the lesion site. | Human brain tissue and animal models of stroke. | [117,118,119,120] |
Inhibition of TNF-α reduces infarct size and neuroinflammation. | Stroke mouse models. | [122,123,124,125] | |||
TNFR1 | CNS | TNFR1 knockout mice have larger infarct sizes compared to wild-type and TNFR2 knockout mice. | Stroke mouse model. | [134,135] | |
TNFR1 is responsible for expression of neuroprotective factors upon ischemia. | Stroke mouse model. | [135,136] | |||
Absence of TNFR1 reduces retinal ischemia-reperfusion damage. | Mouse retinal ischemia-reperfusion model. | [16] | |||
TNFR1 signaling causes neuroinflammation and neurovascular damage in the immature brain. | LPS-sensitized hypoxic-ischemia mouse model. | [138] | |||
TNFR2 | CNS | Absence of TNFR2 aggravates retinal ischemia-reperfusion damage. | Mouse retinal ischemia-reperfusion model. | [16] | |
TNFR2 silencing increases cell injury upon hypoxic conditions. | SH-SY5Y cell line. | [100] | |||
TNFR2 signaling can result in inflammatory ischemia. | Stroke mouse model. | [137] | |||
TNFR1 and TNFR2 | CNS | Deletion of both TNFRs aggravates neuronal damage. | Stroke mouse model. | [5] | |
Multiple sclerosis (MS) | TNF-α | CNS | TNF-α levels are increased in MS lesions. | Human MS brain tissue. | [140,141] |
Constitutive TNF-α overexpression can cause a spontaneous inflammatory demyelinating disorder. | TNF-overexpressing mouse model. | [142] | |||
TNF-α knockout increases demyelination and inflammation. | EAE mouse model. | [144,145] | |||
TNF-α knockout delays both demyelination and remyelination. | Cuprizone mouse model. | [146] | |||
General blockage of TNF-α by etanercept is linked to onset of MS in human case reports. | Human case reports. | [157,158] | |||
General blockage of TNF-α by lenercept may exacerbate symptoms in human MS patients. | Human MS patients. | [156] | |||
TNFR1 | CNS | TNFR1 knockout mice do not develop EAE or have a less severe disease course. | EAE mouse model. | [18,152,153,154] | |
TNFR1 signaling induces oligodendrocyte apoptosis and primary demyelination. | TNF-transgenic mice. | [147] | |||
TNFR1 may contribute to inflammatory infiltration of the spinal cord. | EAE mouse model. | [148] | |||
Selective inhibition of TNFR1 signaling ameliorates EAE-induced pathology. | EAE mouse model. | [18,149] | |||
sTNF-α inhibition protects against EAE symptoms. | EAE mouse model. | [150,151] | |||
TNFR2 | CNS | TNFR2 knockout mice show aggravated demyelination and disease symptoms. | EAE mouse model. | [18,152,153,154] | |
TNFR2 signaling mediates remyelination and oligodendrocyte precursor cell proliferation. | Cuprizone mouse model. | [146] | |||
Selective stimulation of TNFR2 protects primary oligodendrocytes from oxidative stress. | Primary oligodendrocyte cell culture. | [155] |
3.5. Other Neurodegenerative Disorders
4. TNFR1- and TNFR2-Mediated Signaling in Neurodegeneration
4.1. TNFR1—Possible Downstream Targets in Neurodegeneration
4.2. TNFR2—Possible Downstream Targets in Neurodegeneration
5. Complex matters: TNFR1 Signaling Is Primarily Damaging and TNFR2 Beneficial?
5.1. Selective Harmful Downstream Targets of TNFR1 and Beneficial Downstream Targets of TNFR2?
5.2. Soluble TNF Receptors
5.3. Interaction between TNFR2 and Interleukin-17 Receptor D
6. Targeting TNF-α Signaling: An Opportunity for Treatment of Neurodegenerative Disorders?
6.1. Targeting TNF-α as Treatment for Neurodegenerative Disorders
6.2. Targeting TNFRs as Treatment for Neurodegenerative Disorders
7. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Dong, Y.; Dekens, D.W.; De Deyn, P.P.; Naudé, P.J.W.; Eisel, U.L.M. Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders. Antibodies 2015, 4, 369-408. https://doi.org/10.3390/antib4040369
Dong Y, Dekens DW, De Deyn PP, Naudé PJW, Eisel ULM. Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders. Antibodies. 2015; 4(4):369-408. https://doi.org/10.3390/antib4040369
Chicago/Turabian StyleDong, Yun, Doortje W. Dekens, Peter Paul De Deyn, Petrus J. W. Naudé, and Ulrich L. M. Eisel. 2015. "Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders" Antibodies 4, no. 4: 369-408. https://doi.org/10.3390/antib4040369
APA StyleDong, Y., Dekens, D. W., De Deyn, P. P., Naudé, P. J. W., & Eisel, U. L. M. (2015). Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders. Antibodies, 4(4), 369-408. https://doi.org/10.3390/antib4040369