Inhibition of Moesin and CD44 in stem cell-derived neurons affects the pathological genetic signature associated with Alzheimer's disease.

INTRODUCTION

Post mortem proteomic analysis of Alzheimer's disease (AD) brain tissue has identified novel target genes and proteins for potential therapeutic development. Moesin (MSN) and CD44 were identified as candidate targets. Using human induced pluripotent stem cells (hiPSCs)-derived neurons, we assayed how reducing gene expression of MSN and CD44 affected amyloid beta secretion, tau phosphorylation, and transcriptional state.

METHODS

Knockdown of MSN and CD44 in hiPSC-derived neurons was performed using short hairpin RNA (shRNA). Amyloid precursor protein processing and intracellular tau phosphorylation was measured using chemiluminescent ELISA assays. Global gene expression was analyzed by bulk RNA sequencing (RNA-seq).

RESULTS

Knockdown of CD44 and MSN increased secretion of amyloid beta and soluble APP beta and differentially altered tau generation and phosphorylation. RNA-seq revealed diverse effects of CD44 and MSN knockdown and the reversal of some expression shifts found in late-onset AD.

DISCUSSION: These findings connect reduced CD44 and MSN expression to AD-related signatures in neurons and inform their role in the disease.