miR-133b as a potential regulator of a synaptic NPTX2 protein in Alzheimer's disease

Abstract

A synaptic protein, Neuronal Pentraxin 2 (NPTX2), has emerged as a pivotal biomarker for Alzheimer's dementia (AD). We identified candidate miRNAs targeting NPTX2 and performed association and mediation analyses using multi-omics data (N = 702). Among 44 candidate miRNAs, miR-133b was significantly associated with AD and Braak positivity. Higher miR-133b expression was also associated with higher NPTX2 gene expression and better cognition. Mediation analysis showed that miR-133b partially influences AD and cognition through the NPTX2 protein. Our integrated approach suggests a potential role of miR-133b in synaptic integrity and offers new insights into AD pathogenesis.

Figure 1

Association analysis results of miR‐133b expression levels with NPTX2 protein and gene expression levels, AD diagnosis, cognition, and pathological traits. (A) The scatter plot represents a correlation between miR‐133b expression levels and NPTX2 protein levels. The gray zone around the linear regression line represents the 95% confidence interval. (B) Violin and box plots represent miR‐133b expression levels for the AD diagnosis, CERAD positivity, and Braak positivity groups. (C and D) The scatter plots represent correlations between miR‐133b expression levels and NPTX2 gene expression levels (C), as well as between mir‐133b expression levels and global cognition at the last visit (D). The gray zone around the linear regression line represents the 95% confidence interval. AD, Alzheimer's dementia; CERAD, Consortium to Establish a Registry for Alzheimer's Disease; miR, microRNA; NCI, no cognitive impairment; NPTX2, neuronal pentraxin 2. Significance stars indicating the p values of the correlations. *p‐value <0.05. ***p‐value <0.001.

Figure 2

Mediation analysis results of miR‐133b expression levels on AD diagnosis and cognition through NPTX2 protein levels. (A and B) Mediation analysis shows total, direct, and indirect effects of miR‐133b expression levels on AD (A) and a composite Z score of global cognition at the last visit (B) through NPTX2 protein levels, adjusting for age, sex, study (ROS and MAP), RNA integrity numbers, postmortem interval, and years of education, where appropriate. AD, Alzheimer's dementia; MAP, Memory and Aging Project; miR, microRNA; NCI, no cognitive impairment; NPTX2, neuronal pentraxin 2; ROS, Religious Orders Study.