Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Assessing Aβ-independent effects of Module 42 on immune function in vitro.
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Ajith Ishita, Bakshi Souvika, Mead Emma, Gileadi Opher, Katis Vittorio L, Brennan Paul E, Emory‐Sage‐SGC‐Jax TREAT‐AD Center, Gospodinova Katerina O
Аннотация
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.
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.