Abstract
Background
Cognitive decline and memory impairment are frequently observed in Alzheimer's disease (AD) patients and are closely associated with dysfunctional autophagy and neuroinflammation, which subsequently result in neuronal apoptosis and synaptic damage. Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of AD and may play a pivotal role in the early stages of the disease.
Objectives
To examine the role of a miR-4763-3p antagomir in ameliorating cognitive decline in mild cognitive impairment (MCI)-AD mice and to elucidate the underlying mechanisms involved.
Methods
Fluorescence in situ hybridization was used to demonstrate that miR-4763-3p is highly expressed in postmortem hippocampal tissue from AD patients and colocalizes with the Aβ and Tau proteins. Stereotactic injection of the miR-4763-3p antagomir and subsequent behavioral experiments revealed its ability to ameliorate cognitive decline in AD-MCI mice. RNA-seq, tissue staining, and SH-SY5Y cell experiments were used to explore specific molecular mechanisms and associated signaling pathways.
Results
The miR-4763-3p antagomir targeted ATP11A to enhance inward flipping of the "eat me" phosphatidylserine signal on the surface of neuronal cells, effectively alleviating brain inflammation and neuronal loss and improving synaptic morphology in AD-MCI mice. Furthermore, the miR-4763-3p antagomir increased autophagy in the early-stage AD-MCI brain, promoted the clearance of Aβ proteins, and reduced the deposition of lipofuscin. These findings confirm that miR-4763-3p targets ATP11A to regulate the PI3K/AKT/mTOR/Bcl2 signaling pathway, thereby promoting neuronal autophagy and reducing apoptotic crosstalk.
Conclusions
The miR-4763-3p antagomir has the potential to reverse neuronal apoptosis and enhance autophagy levels, improving the inflammatory microenvironment in brain tissue and thus improving learning and memory in early-stage AD-MCI mice to mitigate cognitive decline. Our data offer a promising strategy for the treatment of AD-MCI patients.