Search

Nuclear paraspeckles assembly transcript 1 (NEAT1) is a well-known long noncoding RNA (lncRNA) with various functions in different physiological and pathological processes. Notably, aberrant NEAT1 expression is implicated in the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanism of NEAT1 in AD remains poorly understood. In this study, we investigated that NEAT1 regulated microtubules (MTs) polymerization via FZD3/GSK3β/p-tau pathway. Downregulation of NEAT1 inhibited Frizzled Class Receptor 3 (FZD3) transcription activity by suppressing H3K27 acetylation (H3K27Ac) at the FZD3 promoter. Our data also demonstrated that P300, an important histone acetyltransferases (HAT), recruited by NEAT1 to bind to FZD3 promoter and mediated its transcription via regulating histone acetylation. In addition, according to immunofluorescence staining of MTs, metformin, a medicine for the treatment of diabetes mellitus, rescued the reduced length of neurites detected in NEAT1 silencing cells. We suspected that metformin may play a neuroprotective role in early AD by increasing NEAT1 expression and through FZD3/GSK3β/p-tau pathway. Collectively, NEAT1 regulates microtubule stabilization via FZD3/GSK3β/P-tau pathway and influences FZD3 transcription activity in the epigenetic way.

Nuclear paraspeckles assembly transcript 1 (NEAT1) is a well-known long noncoding RNA (LncRNA) with unclear mechanism in Alzheimer’s disease (AD) progression. Here, we found that NEAT1 down-regulates in the early stage of AD patients and APPswe/PS1dE9 mouse. Moreover, knockdown of NEAT1 induced de-polymerization of microtubule (MT) and axonal retraction of nerve cells by dysregulation of the FZD3/GSK3β/p-tau signaling pathway. Histone acetylation analysis at the Frizzled Class Receptor 3 (FZD3) promoter shows a marked decreased in the levels of the H3K27 acetylation (H3K27Ac) after NEAT1 knockdown. Our data demonstrates that P300/CBP recruited by NEAT1 to the FZD3 promoter and induced its transcription via histone acetylation. In recent years a growing number of evidences have shown an abnormal brain glucose homeostasis in AD. In the present study we also observed an abnormal brain glucose homeostasis and enhanced sirtuin1 (SIRT1) activity after knockdown of NEAT similarly as in AD. Our results provided insight into the role of NEAT1 in the maintenance of MT stability and its effect on glucose metabolism during early stages of AD.