An intronic ncRNA-dependent regulation of SORL1 expression affecting Aβ formation is upregulated in post-mortem Alzheimer's disease brain samples

Abstract

Summary Recent studies indicated sortilin-related receptor 1 (SORL1) to be a risk-gene for late-onset Alzheimer's Disease (AD), although its role in the aetiology and/or progression of this disorder is not fully understood. Here, we report the finding of a novel non-coding (nc) RNA (hereafter referred to as 51A) that maps in antisense (AS) configuration in intron 1 of SORL1 gene. 51A expression drives a splicing shift of SORL1 from the synthesis of the canonical long protein variant 1 to an alternatively spliced protein form. This process, resulting in a decreased synthesis of SORL1 variant 1, is associated with an impaired processing of APP, leading to increase of Aβ formation. Interestingly, we found that 51A is expressed in human brains, being frequently up-regulated in cerebral cortices from Alzheimer's disease patients. Altogether these findings document a novel ncRNA-dependent regulatory pathway that might have relevant implications in neurodegeneration.