Role of necroptosis in the pathogenesis of alzheimer{u2019}s disease and possible effect of certain necroptosis inhibitors / Zeinab Mohamed Abdelnasser ; Supervised Tarek M. Kamal Motawi , Nancy Nabil Shahin

Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Biochemistry

Alzheimer's disease (AD) is a progressively debilitating neurodegenerative disorder that has no effective remedy, so far, with available therapeutic modalities being only symptomatic and of modest efficacy. Necroptosis is a form of controlled cell death with a recently emerging link to the pathogenesis of several neurodegenerative diseases. This study investigated the role of necroptosis in the pathogenesis of AD and evaluated the potential beneficial effect of the necroptosis inhibitors, necrostatin-1 (Nec-1), necrosulfonamide (NSA) and gambogic acid (GA), in a rat model of AD. AD was induced by oral administration of AlCl3 (17 mg/Kg/day) for 6 consecutive weeks. Administration of Nec-1 (1.65 mg/Kg/day), NSA (1.65 mg/Kg/day) intraperitoneally and GA (2.5 mg/Kg/day) subcutaneously for 6 weeks significantly amended AlCl3-induced spatial learning and memory deficits, as demonstrated by enhanced rat performance in Morris water and Y-mazes. Nec-1, NSA and GA alleviated the abnormally high hippocampal expression of tumor necrosis factor-alpha (TNF-Ü), Ý-site amyloid precursor protein cleaving enzyme 1(BACE1), Ý-amyloid, glycogen synthase kinase-3Ý (GSK-3Ý), phosphorylated tau protein, and acetylcholinesterase with concordant replenishment of acetylcholine. The alterations accomplished by Nec-1 and GA on AD disorders were associated with their inhibitory effect on the phosphorylation of the key necroptotic mediator, receptor interacting protein kinase 1 (RIPK1), while the amendments of AD perturbations achieved by NSA correlated with its inhibitory effect on the phosphorylation of the key necroptotic executioner, mixed lineage kinase domain-like protein (MLKL)

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