Translating TNFR signalling into neuroprotective strategies: Proof of concept in acute in vivo models of neurodegeneration using humanized TNFR mice

• DOI: 10.1096/fasebj.30.1_supplement.993.13
• Publication Date: 2023-11-26T16:23:51Z
• Authors: Ulrich L. M. Eisel; Yun Dong; Roman Fischer; Pieter Naudé; Olaf Maier; Csaba Nyakas; Eddy van der Zee; Eric Guenzi; Andreas Herrmann; Roland Kontermann; Klaus Pfizenmaier

TNF is involved in several degenerative brain diseases including stroke, Multiple Sclerosis, Parkinson's disease and Alzheimer's (AD). It became apparent recent years that TNFR1 TNFR2 signalling diverges with respect to its involvement neurodegeneration neuroprotection, respectively (Fontaine et al., 2002; Marchetti 2004; Dolga 2008; 2009; Fischer 2011; Naudé 2012; Maier 2013). Under chronic stimulation mediated counteracts pro‐apoptotic pathways by the activation of a PI3K, PKB/Akt dependent NF‐kB pathway. This allows neuronal survival despite exposure lethal concentrations neurotoxins such as glutamate (NMDA) or oligomeric forms Amyloid beta. Both agents are known be cell loss course disease. Consequently new compounds have been developed – instead targeting itself selectively target potential therapeutics human neurodegenerative diseases. Here we show results blocking either activating mouse model humanized TNFRs. For generating TNFR mice used gene replace extracellular domains genes their counterpart. Loss cholinergic innervation one earliest hallmarks AD, which leads severe cognitive impairment. Cholinergic neurons project fibres from Nucleus Basalis Meynert (NBM) into hippocampus prefrontal cortex. Therefore NBM will reduce fibre density cortex lead memory learning deficits. We established lesion investigate vivo therapeutic role antagonists agonists. By using optical measurements stained microglial sections were able quantify amount eight days upon delivery toxic dose NMDA basalis via stereotactic injection. Controlateral damage was internal standard. Behavioural testing performed assess function. Our suggest both, TNFR2, neuroprotection this acute lesioning model, serves paradigm for AD. Support Funding Information Parts work funded EU FP6 NeuroproMiSe, ZonMW Deltaplan Dementie Memorabel Program, Internationale Stichting Alzheimer Onderzoek, Netherlands, Carl‐Zeiss‐Stiftung, Hertie Stiftung, BMBF, Germany.