Stimulation of TNF receptor 2 as effective therapeutic for Alzheimer's disease

Projectdetails

Omschrijving

Alzheimer’s disease (AD) is the most common cause of dementia in individuals over 60 years of age and, thus, an urging health issue and socioeconomic burden for the ageing societies in Europe and worldwide. The molecular and cellular impairments leading to manifestation of the disease are still poorly understood and, thus, causal therapies are not available.
Recent advances in our understanding strongly indicate that neuroimmune processes in the brain play a key role in the development of pathophysiological changes in AD. TNF-a is an inflammatory cytokine with diverse functions in the healthy and diseased brain. Evidence for the involvement of TNF-a in AD emanates from various research disciplines. TNF-a exerts pro-apoptotic or potent neuroprotective effects in neurons, which is mainly dependent on the signaling via its receptors. In fact, neurodegeneration was associated with signaling of the soluble form of TNF (sTNF) through TNFR1, whereas neuroprotection could be associated with TNFR2 signaling induced by the membrane form of TNF-a (mTNF) (Fontaine et al., 2002; Marchetti et al., 2004). Convincing evidence from transgenic AD mouse models with amyloid pathology shows that deletion of TNFR1 or enhanced stimulation of TNFR2 protects cognitive impairment and amyloid beta associated neuropathology (He et al., 2007; Jiang et al., 2014; Montgomery et al., 2011). Thus selective targeting of TNF-a receptors is a promising treatment strategy for AD. In this respect, we recently showed that novel human specific TNFR-selective therapeutics, i.e., a TNFR1 antagonist and a TNFR2 agonist, block neuroinflammation and promote neuronal survival in a mouse model of NMDA-induced acute neurodegeneration in mice carrying a knock-in with humanized extracellular domains of TNFRs (Dong et al., 2016). Our findings clearly proof that neuronal survival depends on TNFR2 stimulation. We therefore hypothesize that selective targeting of TNFR2 is a promising therapeutic strategy to abrogate AD-associated neurodegeneration and cognitive impairments.
StatusGeëindigd
Effectieve start/einddatum01/01/201801/01/2022

VN Doelstellingen voor duurzame ontwikkeling

In 2015 stemden de VN-lidstaten in met 17 wereldwijde duurzame ontwikkelingsdoelstellingen (Sustainable Development Goals, SDG's) om armoede te beëindigen, de planeet te beschermen en voor iedereen welvaart te garanderen. Dit project draagt bij aan de volgende duurzame ontwikkelingsdoelstelling(en):

  • SDG 3 – Goede gezondheid en welzijn

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