miR-125b promotes tau phosphorylation by targeting the neural cell adhesion molecule in neuropathological progression

• MicroRNAs, small noncoding RNAs, not only regulate gene expression at the post-transcriptional level in a variety of physiological processes but also accompany the initiation and progression of a vast number of diseases, including dementia. While miR-125b has been shown to be aberrantly expressed in some dementia patients, its role in the pathological process remains ambiguous. Presenilin-1/2 conditional double knockout mice exhibit a range of symptoms, including impaired cognition and memory, increased tau phosphorylation, neuroinflammation, and apoptosis, and are therefore regarded as a useful dementia model. In the prefrontal cortices of double knockout mice, miR-125b was found to be abnormally increased in an age-dependent manner. We further verified the neural cell adhesion molecule (NCAM) as an miR-125b target using the dual luciferase reporter assay. The NCAM protein level was decreased when miR-125b was overexpressed (OE) in neuronal growth factor-induced differentiated PC12 cells, which further inhibited the neuronal growth factor-induced phosphorylation of glycogen synthase kinase 3 beta (GSK beta) at the Ser9 site and ultimately increased the GSK3 beta activity and tau phosphorylation. Moreover, on serum deprivation, high GSK3 beta activity in differentiated miR-125b-OE PC12 cells induced increased caspase-3 activation. Finally, adeno-associated virus-mediated miR-125b overexpression in the prefrontal cortexes of wild-type C57B/L6 mice resulted in decreased dendritic spine density. In addition, similar to the in vitro data, elevated GSK3 beta activity and hyperphosphorylation of the tau protein were confirmed. Taken together, our findings reveal a direct regulation of miR-125b on NCAM, which leads to further effects on downstream GSK3 beta activity and tau phosphorylation and may contribute to the generation of neurofibrillary tangles in neuropathological progression. 

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

miR-125b

NCAM

GSK3 beta

p-Tau

Presenilin-1/2

Dementia

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