The role of TNF in in vitro and in vivo models of neurodegeneration

Abstract

Using our novel engineered dominant negative Tumor Necrosis Factor variants (DN-TNFs) in models of Parkinson’s Disease (PD) and Alzheimer’s Disease (AD), we are identifying TNF-dependent signaling mechanisms that elicit death of DA neurons as well as TNF-dependent microglial activities that exacerbate amyloid beta-associated neurotoxicity and death of cholinergic neurons. In mouse models of AD, peripheral inflammation (LPS) exacerbates amyloid and tau pathology in hippocampus; we investigated whether blocking soluble TNF signaling with the infusion of DN-TNFs could block the progressive neuropathology or ameliorate the LPS effects. Inhibition of TNF signaling in vitro with DN-TNFs attenuates LPS- induced microglia activation and loss of DA neurons; delayed TNF inhibition still rescues DA neurons and provides more robust rescue than anti-oxidant pretreatment. Experiments are underway to investigate which signaling pathways transduce the neuroinflammatory and neurotoxic effects of TNF. In vivo, unilateral intrastriatal injections of 6-OHDA or intranigral chronic low dose LPS infusion result in a 70–80% loss of ipsilateral nigral DA neurons. Co-administration of DN-TNFs on the lesion side reduces neuronal loss by half and attenuates ipsiversive circling behavior. These results suggest that targeting the TNF pathway may be a reasonable therapeutic approach to halt or slow the progressive loss of DA neurons in PD. Funding by MJ Fox Foundation, American Health Assistance Foundation, and The University of Texas Southwestern Medical Center at Dallas Alzheimer’s Disease Center; NIH,NIA P30AG12300.