miR-143-3p Inhibits Aberrant Tau Phosphorylation and Amyloidogenic Processing of APP by Directly Targeting DAPK1 in Alzheimer’s Disease

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.

Targeting Death-Associated Protein Kinases for Treatment of Human Diseases: Recent Advances and Future Directions

“…Recently, miR-143-3p was reported to bind to the 3′ untranslated region of DAPK1 mRNA to inhibit its translation, thereby attenuating the phosphorylation of APP and reducing the production of Aβ 40 and Aβ 42 . 133 In addition, miR-143-3p reduced tau protein phosphorylation and promoted neural bump and microtubule assembly. The expression of miR-143-3p and DAPK1 were negatively correlated.…”

“…The expression of miR-143-3p and DAPK1 were negatively correlated. Therefore, miR-143-3p may play a role in regulating the abnormal tau phosphorylation and amyloidosis process of APP by targeting DAPK1, and this regulatory mechanism may grant a new strategy for AD treatment 133 (Table 3). Apart from regulating APP and tau, DAPK1 is also involved in neurotoxic agents such as ceramide or neuronal cell death in animal models of AD.…”

“…Thus, knockdown of DAPK1 expression significantly inhibits Aβ 40 and Aβ 42 secretion. Recently, miR-143-3p was reported to bind to the 3′ untranslated region of DAPK1 mRNA to inhibit its translation, thereby attenuating the phosphorylation of APP and reducing the production of Aβ 40 and Aβ 42 . In addition, miR-143-3p reduced tau protein phosphorylation and promoted neural bump and microtubule assembly.…”

“…The expression of miR-143-3p and DAPK1 were negatively correlated. Therefore, miR-143-3p may play a role in regulating the abnormal tau phosphorylation and amyloidosis process of APP by targeting DAPK1, and this regulatory mechanism may grant a new strategy for AD treatment (Table ).…”

Bibliometric analysis of research on Alzheimer’s disease and non-coding RNAs: Opportunities and challenges

“…Indeed, the role of ncRNAs in nervous system diseases has been further refined, and in-depth studies on the physiological functions of a specific ncRNA have gradually shown a potential correlation with AD ( Jiang et al, 2022 ). For example, miR-143-3p has been found to inhibit abnormal Tau phosphorylation in AD and amyloid processing in amyloid precursor protein ( Wang L. et al, 2022 ).…”