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miR-143-3p Inhibits Aberrant Tau Phosphorylation and Amyloidogenic Processing of APP by Directly Targeting DAPK1 in
Long Wang1, Xindong Shui1, Yingxue Mei1
1Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.
Abstract:
The neuropathology of Alzheimer's disease (AD) is characterized by intracellular aggregation of hyperphosphorylated tau and extracellular accumulation of beta-amyloid (Aβ). Death-associated protein kinase 1 (DAPK1), as a novel therapeutic target, shows promise for the treatment of human AD, but the regulatory mechanisms of DAPK1 expression in AD remain unclear. In this study, we identified miR-143-3p as a promising candidate for targeting DAPK1. miR-143-3p directly bound to the 3' untranslated region of human DAPK1 mRNA and inhibited its translation. miR-143-3p decreased tau phosphorylation and promoted neurite outgrowth and microtubule assembly. Moreover, miR-143-3p attenuated amyloid precursor protein (APP) phosphorylation and reduced the generation of Aβ40 and Aβ42. Furthermore, restoring DAPK1 expression with miR-143-3p antagonized the effects of miR-143-3p in attenuating tau hyperphosphorylation and Aβ production. In addition, the miR-143-3p levels were downregulated and correlated inversely with the expression of DAPK1 in the hippocampus of AD patients. Our results suggest that miR-143-3p might play critical roles in regulating both aberrant tau phosphorylation and amyloidogenic processing of APP by targeting DAPK1 and thus offer a potential novel therapeutic strategy for AD.
Insights
MicroRNA-143-3p targets DAPK1, reducing Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) pathology involves tau hyperphosphorylation and beta-amyloid (Aβ) accumulation.
- Death-associated protein kinase 1 (DAPK1) is a potential therapeutic target for AD, but its regulatory mechanisms are unknown.
Purpose of the Study:
- To investigate the role of miR-143-3p in regulating DAPK1 expression and its impact on Alzheimer's disease pathology.
- To explore miR-143-3p as a potential therapeutic strategy for AD.
Main Methods:
- Investigated the direct binding of miR-143-3p to DAPK1 mRNA.
- Assessed the effects of miR-143-3p on tau phosphorylation, neurite outgrowth, microtubule assembly, and amyloid precursor protein (APP) processing.
- Analyzed miR-143-3p and DAPK1 levels in the hippocampus of AD patients.
Main Results:
- miR-143-3p directly targets and inhibits DAPK1 translation.
- miR-143-3p reduces tau phosphorylation, promotes neurite outgrowth, and enhances microtubule assembly.
- miR-143-3p attenuates APP phosphorylation and decreases Aβ generation.
- Downregulation of miR-143-3p and inverse correlation with DAPK1 expression observed in AD patient hippocampi.
Conclusions:
- miR-143-3p plays a critical role in regulating tau phosphorylation and APP processing by targeting DAPK1.
- miR-143-3p represents a potential novel therapeutic strategy for Alzheimer's disease.
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