Human DDIT4L intron retention contributes to cognitive impairment and amyloid plaque formation

Abstract

AbstractCognitive impairment and amyloid plaques are the most important clinical and neuropathological feature for dementia, especially in Alzheimer’s disease (AD). However, the etiology of dementia is complicated. The present study reveals that an aberrant splicing of DDIT4L, the isoform DDIT4L intron retention (DIR), occurs in AD patients. Homozygous DIR-knock-in (KI) mice showed DIR expression in hippocampal neurons, marked cognitive impairment, augmented Aβ deposition and enhanced Tau phosphorylation. The DIR colocalized with thioflavin S-positive plaques and gelsolin in AD patients. The DIR induced Aβ deposition and cognitive impairment by interacting with gelsolin. Moreover, DIR interacted with GluA1, the subunit of the AMPA receptor, contributing to synaptic deficiency and cognitive impairment. Furthermore, an anti-DIR monoclonal antibody (mAb) alleviated cognitive impairment and reduced Aβ deposition and Tau phosphorylation. Thus, DIR contributes to cognitive impairment and amyloid plaques, and could be a potential therapeutic target for dementia.