Assessing Aβ‐independent effects of Module 42 on immune function in vitro

Journal article

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 Ca2+ 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 Ca2+ signaling. MDK and TMEFF2 ectodomain had an effect on both phagocytosis and Ca2+ signaling.

Authors: Ajith, I; Bakshi, S; Mead, E; Gileadi, O; Katis, VL

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Alzheimer's & Dementia: The Journal of the Alzheimer's Association
• Volume: 22
• Issue: 2
• Article number: e71215
• Publication date: 2026-02-25
• Acceptance date: 2026-01-22
• DOI: 10.1002/alz.71215
• EISSN: 1552-5279
• ISSN: 1552-5260
• Language: English
• Keywords: Alzheimer's disease; M42 proteins; matrisome; immune function