Decreased miR-132 plays a crucial role in diabetic encephalopathy by regulating the GSK-3β/Tau pathway

Abstract

Diabetic encephalopathy (DE) is a global concern and Gordian knot worldwide. miRNA-132 (miR-132) is a class of negative gene regulators that promote diabetic pathologic mechanisms and its complications. However, the molecular mechanisms of miR-132 in DE are elusive, thus an alternative therapeutic strategy is urgently in demand. The present study explored the protective effect and the underlying mechanism of miR-132 on DE via the GSK-β/Tau signaling pathway. Experimentally, a type 2 DM rat model was developed by incorporating a high-fat diet and streptozotocin injection. Further, the DE model was screened via the Morris Water Maze test. Primary hippocampal neurons and HT-22 cells were used for in vitro analysis. We found that hyperglycemia exacerbates cognitive impairment in T2DM rats. When we isolated the primary hippocampus neurons, the expression of miR-132 RNA was low in both the DE hippocampus and primary neurons. GSK-3β and Tau 404 were highly expressed in injured HT-22 cells and diabetic hippocampal tissues. miR-132 downregulated the expression of GSK-3β. Besides, a binding and colocalized relationship between GSK3β and Tau was also reported. These findings suggest that miR-132 exerts protective effects from DE injury by repressing GSK-3β expression and alleviating Tau hyperphosphorylation in HT-22 cells and hippocampus tissues.

mTOR-dependent TFEB activation and TFEB overexpression enhance autophagy-lysosome pathway and ameliorate Alzheimer's disease-like pathology in diabetic encephalopathy

“…Moreover, the T2DM group showed increased latency of first arrival to the targeted platform and decreased time spent in the targeted platform quadrant and frequency of entrance into the platform zone during the probe trials (Fig. 1 D–F), consistent with previous findings [ 42 , 43 ], indicating impaired spatial memory in T2DM mice.

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Association of Polymorphisms within HOX Transcript Antisense RNA (HOTAIR) with Type 2 Diabetes Mellitus and Laboratory Characteristics: A Preliminary Case-Control Study

“…TNFA contributes to the pathogenesis of a variety of inflammatory diseases as well as type 1 diabetes mellitus (T1DM) in children and adolescents [ 57 , 58 ]. Irregularity in GSK-3 β gives rise to diabetic encephalopathy [ 59 ], diabetic cardiomyopathy [ 60 ], maternal type 1 diabetes [ 61 ], T1DM [ 62 ], and other types of diabetes [ 63 ]. Jiang et al proposed that HOTAIR downregulation is associated with decreased expression of insulin-like growth factor-1 (IGF-1) [ 64 ].…”

Diverse and Composite Roles of miRNA in Non-Neuronal Cells and Neuronal Synapses in Alzheimer’s Disease

“…miR-132 directly targets the polypyrimidine tract-binding protein 2 (PTBP2) in the neurons to aberrantly splice tau exon 10, leading to an imbalance in the ratio of three-repeat (3R) and four-repeat (4R) tau isoforms [ 91 ]. miR-132 prevents microtubule dynamics and neurofibrillary tangle (NFT) accumulation to enhance LTP in the P301S tau transgenic mice by directly targeting the RNA-binding protein RNA Binding Fox-1 Homolog 1 (RBFOX1) to degrade tau mRNA, acetylation via EP300, cleavage via calpain 2 and caspases 3/7, and tau kinase glycogen synthase kinase 3β (GSK3β), which hyperphosphorylates tau [ 69 ] to disrupt microtubule dynamics and NFT accumulation [ 93 ]. In addition to this, miR-132 can target glycosyltransferase-like domain containing 1 (GTDC-1), indirectly inhibiting the tau kinase cyclin-dependent kinase 5 (CDK5) through the NOS1 signaling pathway [ 94 ].…”