MicroRNA-128 ameliorated cognitive deficits and reduced amyloid-beta deposition by inhibiting APPBP2 and mTOR in a mouse model of Alzheimer's disease

Abstract

Alzheimer’s disease (AD), the most common form of dementia in an aged population, is characterized by the neuropathological deposition of amyloid plaques composed of amyloid-beta (Aβ) peptides and neurofibrillary tangles accumulated by hyperphosphorylated tau. Although the exact molecular mechanism underlying AD remains unclear, numerous studies have verified that the abnormal accumulation of Aβ peptides and hyperphosphorylated tau play important roles in AD pathogenesis, which can induce a series of neurotoxic processes including microglia activation, neuroinflammation, synaptic loss, and neuron death. MicroRNAs (miRNAs) are endogenous small noncoding RNAs that repress protein expression by binding to the 3′ untranslated region of target messenger RNAs. Recent studies have suggested the important roles of miRNAs in AD by demonstrating that many miRNAs were dysregulated in AD patients as well as AD mouse models, and that several miRNAs could regulate the expression of genes involved in AD pathogenesis. Increasing evidence reveals that restoring or reversing dysregulated miRNAs can counteract AD neuropathology, suggesting new therapeutic strategies by modulating those dysregulated miRNAs in AD. Herein, we performed a screening of several miRNAs in plasma samples of AD patients and age and sex matched controls, with the purpose of identifying miRNAs whose expression would alter in AD. We found a significant reduction of miR-128 in AD plasma, as well as in AD transgenic mouse models and cellular models. Moreover, the downregulation of miR-128 was significantly associated with lower mini-mental status examination scores, and decreased Aβ42/Aβ40 ratio but increased total tau and phosphorylated tau levels in cerebrospinal fluid. Both gain-of-function and loss-of-function studies of in vitro cellular models demonstrated that miR-128 not only repressed tau phosphorylation, but also reduced Aβ levels. Further investigation revealed that miR-128 could directly inhibit the expression of GSK3β, an important kinase that can phosphorylate tau, and it also could directly suppress the expression of APPBP2, an important regulator for Aβ formation, and mTOR, a critical negative modulator for autophagy. In vivo restoration of miR-128 by administering miR-128-expressing adeno-associated virus in the hippocampus of 5XFAD mice ameliorated cognitive deficits and reduced amyloid plaques deposits. In addition, we also clarified that C/EBPα was essential for MIR128-1 transcription, but its expression was repressed by Aβ, which might represent an important mechanism responsible for the reduction of miR-128 in AD. Taken together, our results suggested that miR-128 reduction might contribute to AD progression, while the restoration of miR-128 could be a promising therapeutic strategy.