Abstract:
Alzheimer’s disease (AD), the major cause of dementia, affects elderly population worldwide. Beta amyloid (Aβ) plagues are the main cause in the AD pathology, and removing the plagues is a constant challenge in the treatment of AD. Recently, depletion of receptor interacting protein kinase 1 (RIPK1) activity in murine AD models has been shown to reduce amyloid burden, memory deficits and the levels of inflammatory cytokines. Moreover, inhibition of RIPK1 has been shown to promote microglial degradation of Aβ in vitro. Necroptosis, a programmed form of necrosis, executed by mixed lineage kinase domain-like (MLKL) protein and activated by RIPK1 and RIPK3, has been shown to be involved in AD. However, the role of RIPK1 in Aβ-induced necroptosis is yet to be deciphered. In this study, SH-SY5Y human neuroblastoma cells treated with Aβ 1-40 or Aβ 1-42 was used as an AD model. Caspase activity assay and co-administration with caspase inhibitor or autophagy inhibitor showed that Aβ-induced neuronal cell death was independent of apoptosis and autophagy pathways. Furthermore, immunoblotting assay showed that Aβ-treated cells and cells overexpressing amyloid precursor protein (APP) activated
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RIPK1/MLKL-dependant necroptosis pathway. Moreover, depletion of RIPK1 expression rescued the cells from Aβ-induced neuronal cell death. In addition, ectopic expression of RIPK1 was found to prolong the stability of the endogenous APP. Transcriptomic analysis showed that the expression of RIPK1 was increased in AD patients, particularly in the hippocampus, entorhinal cortex and temporal cortex. Taken together, the present findings show that Aβ is able to activate necroptosis in an RIPK1-MLKL dependent manner, suggesting that RIPK1 plays an important role in the development of AD.
