2026/02/01 by Ishita Ajith, Souvika Bakshi, Emma Mead +4 · 1 voice
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · #Calcium signaling and nucleotide metabolism #Endoplasmic Reticulum Stress and Disease #Phagocytosis and Immune Regulation
paper · doi:10.1002/alz.71215
openalex publication_date 2026/02/01 · openalex created_date 2026/02/26 · openalex updated_date 2026/08/03
Abstract INTRODUCTION A deep multi‐omic analysis of post mortem human brains has identified a new co‐expression protein network – Module 42 (M42), strongly corelated with Alzheimer's disease (AD) pathology. M42 comprises 32 transmembrane and extracellular matrix (ECM)‐associated proteins, including the amyloid precursor protein (APP) and apolipoprotein E (apoE), and its members have been implicated in amyloid beta (Aβ) pathology. We systematically evaluated the Aβ‐independent effects of M42 on immune function in vitro. METHODS Recombinant M42 proteins were expressed and purified. Their effects on phagocytosis, intracellular signaling, and cell viability were assessed in human induced pluripotent stem cell‐derived macrophages. RESULTS Treatment with Midkine (MDK) reduced phagocytosis, while treatment with the ectodomain of Transmembrane protein with EGF‐like and two follistatin‐like domains 2 (TMEFF2) had the opposite effect. Both proteins promoted intracellular Ca 2+ signaling, and TMEFF2 also suppressed Syk kinase activity. No M42 proteins had an effect on viability. DISCUSSION Our results suggest an additional role for M42 in AD via regulating immune functions. Highlights We tested M42 proteins for their effects on immune functions in vitro. Five proteins altered phagocytosis, and seven altered Ca 2+ signaling. MDK and TMEFF2 ectodomain had an effect on both phagocytosis and Ca 2+ signaling.