Investigation of the inhibitory roles of hnRNP A1 in the pathogenesis of Alzheimer's disease

Abstract

Alzheimer’s Disease (AD) is a neurodegenerative disorder. Its major symptoms include loss of memory and impairment of cognition. Extracellular Aβ plaques and intracellular neurofibrillary tangles (NFT) are exceedingly important histopathological hallmarks in AD. Other cellular features of AD include dysfunction of autophagy, neuroinflammation, and oxidative stress. hnRNP A1 is an RNA binding protein. Some previous reports indicated hnRNP A1 might be highly related to AD pathology. However, how hnRNP A1 affect the progression of AD still needs to be demonstrated. In this study, hnRNP A1 was knocked down in AD cellular models through siRNAs. In N2a-APPsw cells, knockdown of hnRNP A1 could increase the expression of ADAM10, which indicated that the degradation of APP through non-amyloidogenic pathway was enhanced. Besides, knockdown of hnRNP A1 could enhance the expression of LC3-Ⅱ, an autophagosome marker, in N2a-APPsw cells. But knockdown of hnRNP A1 could not regulate neuroinflammation or oxidative stress. hnRNP A1 was also knocked down in AD mice models. This lowered AD-related mortality in TgCRND8 mice. In Morris Water Maze test, TgCRND8:hnRNP A1+/- mice and 5XFAD:hnRNP A1+/- mice could perform significantly better than TgCRND8 mice and 5XFAD mice respectively, implicating that knockdown of hnRNP A1 could alleviate cognitive deficits. The amyloid burden in the dentate gyrus of male 5XFAD mice was decreased by downregulation of hnRNP A1. VPC-80051 compound is an hnRNP A1 inhibitor. The results suggested that VPC-80051 could not regulate Aβ pathway or autophagy in N2a-APPsw cells, but was involved in oxidative stress. With the treatment of H2O2, VPC-80051 could lead to the increase of cytoplasmic hnRNP A1. And it could enhance the expression of HO-1, which might be regulated through Nrf2. Besides, VPC-80051 could induce the increase of cytoplasmic hnRNP A1 under the treatment of Aβ oligomers in BV2 cells. And it could lower the level of iNOS, which might be regulated through NF-κB. In conclusion, these results indicated that hnRNP A1 played inhibitory roles in the pathogenesis of Alzheimer’s disease. Both knockdown of hnRNP A1 and inhibiting the activity of hnRNP A1 may help slow down the progression of AD.