MiR-219 deficiency in Alzheimer’s disease contributes to neurodegeneration and memory dysfunction through post-transcriptional regulation of tau-kinase network

Abstract

Intracellular accumulation of hyperphosphorylated misfolded tau proteins is one of the main neuropathological hallmarks in Alzheimer's disease (AD) and related tauopathies. Hence, knowledge and understanding of disease mechanisms altering tau proteostasis and inducing cytotoxicity is critical.MicroRNAs (miRNAs) are capable of binding to and silencing many target transcripts, providing an additional level of regulation that complements canonical transcriptional pathways. Therefore, observed abnormalities in their expression patterns in neurodegeneration suggest alterations of microRNA-target networks as drivers of cellular dysfunction in the disease. Strikingly, here we have found in autopsy brain tissue that miRNA miR-219 expression levels are decreased in a brain region early affected in AD patients, the entorhinal cortex. Our bioinformatics analysis indicates miR-219 is predicted to target Calcium/calmodulin-dependent protein kinase 2 gamma subunit (CAMK2), Tau tubulin kinase 1 (TTBK1) and Glycogen synthase kinase 3 beta (GSK3), which are all implicated in the generation of abnormal hyperphosphorylated tau. We reveal human proteomic data supporting dysregulation in the levels of predicted miR-219 targets in the entorhinal cortex. In mammalian cellular models, we found that downregulation of miR-219 de-repress synthesis of three tau kinases, CAMK2, TTBK1 and GSK3 on the post-transcriptional level resulting in tau phosphorylation and cell toxicity. Finally, we show that deficiency of miR-219 in vivo promotes age dependent neurodegeneration in the adult brain, with enhanced alterations in tau proteostasis, presynaptic terminals and memory impairment. Taken together, our data implicate miRNA dysregulation central to AD etiopathogenesis and suggest potential targets for the treatment of AD and related tauopathies.

MicroRNA: A Key Player for the Interplay of Circadian Rhythm Abnormalities, Sleep Disorders and Neurodegenerative Diseases

“…However, it is of interest to note that common miRNAs are involved in the expression of genes related to circadian rhythm, sleep disorders and AD pathogenesis, indicating the strong connection between them. The overexpression of miR-219 has been observed in the brains of patients with AD, and miR-219 is known to play a role in the downregulation of Tau phosphorylation by targeting GSK-3β [115]. This miRNA has been reported to be a modulator of the circadian clock via the CLOCK and BMAL1 complex [9].…”

Advances and Challenges in Understanding MicroRNA Function in Tauopathies: A Case Study of miR-132/212

“…Nearly 15 miRNAs have been implicated so far in the indirect modulation of tau ( 8 , 25 ). These “tau modifier” genes are mostly kinases, and include Gsk-3β [miR-132 ( 26 ), miR-125b ( 27 ), miR-124 ( 28 ), miR-219 ( 29 , 30 ), miR-138 ( 31 )], Cdk5 [miR-125b ( 32 , 33 ), miR-26b ( 34 ), miR-195 ( 35 )], Erk [miR-125b ( 32 )], Itpkb [miR-132 ( 36 )], Fyn [miR-369 ( 37 ), miR-106b ( 38 )], and Rock1 [miR-146a ( 39 )]. Tau phosphatases include: Ppp1ca [miR-125b ( 32 )] and Ptpn1 [miR-124 ( 40 )].…”