Necroptosis signaling pathways in Alzheimer disease: from mechanisms to therapies
Necroptosis signaling pathways in Alzheimer disease: from mechanisms to therapies
Sara Chavoshinezhad,1,*Esmael Izadpanah,2kambiz hassanzadeh,3
1. Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran 2. Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran 3. Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
Introduction: Alzheimer disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, accounting for 60% to 80% of cases. AD is clinically characterized by cognitive impairments and neuropathologically by the presence of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles. The extensive neuronal loss and atrophy have been detected in the cortex and hippocampus areas of the brains with AD. There is increasing evidence suggesting that activation of necroptosis signaling pathway plays an important role in AD-related neuronal loss. Necroptosis, the most characterized regulated necrosis, is mediated by TNFα binding to TNFR1 followed by assembly of the necrosome complex composed of RIPK1, RIPK3 and MLKL. MLKL then translocates to the plasma membrane and forms pores, leading to membrane rupture and release of intracellular content into the microenvironment. Increased immunoreactivity for pRIPK1, pRIPK3, and pMLKL was observed in AD transgenic mice as well as in AD patients, which were associated with decreased neuronal density and cognitive deficits. Moreover, preclinical studies have shown that genetic or pharmacological inhibition of necrosome components can exert protective effects against learning and memory deficits in several models of AD through reducing Aβ burden, hyperphosphorylated tau protein level, inflammation, and neurodegeneration. More interestingly, clinical studies are designed to assess the efficiency and effectiveness of necroptosis inhibitors in healthy subjects and AD patients. A clinical investigation conducted in the US and the Netherlands have proven that the RIPK1 inhibitor (DNL747) is safe, tolerable and effectiveness in AD patients.
Methods: This abstract is a review type and does not include materials& methods and results section.
Results: This abstract is a review type and does not include materials& methods and results section.
Conclusion: Taken together, targeting necroptosis may provide a promising strategy for the treatment of AD.