Therapeutic strategies for neurodegenerative disorders

Dong, Y. 2017 [Groningen]: University of Groningen. 177 p.

Research output: ScientificDoctoral Thesis

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  • Yun Dong
Neurodegenerative disorders are defined as hereditary and sporadic conditions, which are characterized by progressive nervous system dysfunction or pathological conditions affecting the brain. These disorders, which are often associated with atrophy of the affected central or peripheral structures of the nervous system, including conditions such as Alzheimer's disease (AD) , Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's disease, stroke, as well as brain ischemia and damages of cerebral cortex. In this thesis, we mainly investigated and evaluated effective therapeutic strategies against neurodegeneration in a model of Nucleus Basalis Magnocellularis (NBM) lesions.
Tumor necrosis factor alpha (TNF-α) has been implicated to play a predominant role in neurodegeneration, such as AD, MS and brain ischemia: Whereas TNF-α signalling via TNF receptor 1 leads to aggravation, TNF receptor 2 exerts neuroprotection. Dependent on the opposite roles of TNF-α in neurodegeneration, we here investigated the potential effects of a human specific TNF receptor 1 inhibitor (ATROSAB) and TNF receptor 2 agonists (TNC-scTNF and EHD2-scTNF) in the NBM-lesioned mouse models. As these compounds do not work on mouse TNF receptors, we generated humanized TNF receptor knock-in mice by replacing the extracellular domains of the endogenous mouse TNF receptors by their human counterparts. Using these mice, we found that both compounds significantly reduced damage and inflammation resulting from the NBM lesion and significantly improved cognitive behavioral dysfunctions. Importantly, TNFR2 signalling was found to be essential for neuroprotection. In another study, we found that immunization with Aβ-derived cyclopeptide conjugates representing epitopes mimicking oligomeric Aβ prevented Aβ oligomer-induced NBM lesions in mice. In conclusion we investigated and discussed two different potential therapeutic interventionsin this thesis aimed to treat AD.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
Award date11-Jul-2017
Place of Publication[Groningen]
Print ISBNs978-94-028-0696-0
StatePublished - 2017

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