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P3–265: In vivo and in vitro validation of TNF as a key neuroinflammatory mediator of neurotoxicity and neurodegeneration in models of PD and AD
Author(s) -
Tansey Malu G.,
McAlpine Fiona E.,
McCoy Melissa K.,
Frank-Can Tamy C.,
Meinert Kelly A.,
Botterman Barry R.,
Tansey Keith E.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1534
Subject(s) - microglia , neurodegeneration , neuroinflammation , tumor necrosis factor alpha , neurotoxicity , dopaminergic , cytokine , neuroscience , neuroprotection , in vivo , biology , medicine , pharmacology , immunology , inflammation , dopamine , disease , microbiology and biotechnology , toxicity
Background: Microglia activation and overproduction of inflammatory mediators in the CNS have been implicated in both Parkinson’s (PD) and Alzheimer’s disease (AD). However, key molecular mediators of neurotoxicity that directly contribute to neurodegeneration have not been identified. A role for the pro-inflammatory cytokine tumor necrosis factor (TNF) has been implicated in both PD and AD. Nigral midbrain dopaminergic (DA) neurons and certain populations of cholinergic neurons are extremely sensitive to TNF; and the CSF and post-mortem brains of patients with both diseases display elevated levels of TNF. Methods: Using our engineered dominant negative TNF variants (DN-TNFs) and the decoy receptor etanercept, we found that TNF-dependent mechanisms are required for progressive in vitro and in vivo degeneration of the nigrostriatal pathway. Results: Specifically, inhibition of TNF signaling in vitro with anti-TNF biologics attenuated DA neuron loss even after delayed administration. In vivo, unilateral intrastriatal injections of 6-OHDA or intranigral chronic low dose LPS infusion resulted in a 65-70 % loss of ipsilateral nigral DA neurons; while co-administration of DN-TNFs on the lesion side reduced neuronal loss by half and attenuated ipsiversive circling behavior in 6-OHDA lesioned rats. Experiments are underway to identify targets and signaling pathways that transduce the neurotoxic effects of TNF. Using both primary microglia and the BV2 microglia cell line we are identifying signaling cascades activated by TNF receptors (R1 and R2) that regulate microglial activities and microglial-derived oxidant stress. Results from these studies are providing new clues about the role of TNF in early (pre-plaque) versus late stages (aggressive plaque) of amyloid beta/p-tauassociated neurotoxicity and its contribution to cholinergic neurodegeneration. We hypothesize that TNF contributes to the reported increase in microglial burden and exacerbated hippocampal and entorhinal cortex neuropathology in 3xTgAD following chronic systemic LPS exposure. Therefore, we expect that blocking TNF signaling in vivo in these mice with anti-TNF biologics and lentiviral-derived DN-TNFs will severely blunt the LPS effect. Conclusions: Timely inhibition of the TNF pathway may slow the progressive loss of neurons in both PD and AD. [Funding by MJ Fox Foundation, American Health Assistance Foundation, and UTSW Alzheimer’s Disease Center; NIH, NIA P30AG12300.]