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Assessing Aβ-independent effects of Module 42 on immune function in vitro
Ishita Ajith1,2, Souvika Bakshi1, Emma Mead1,3
1Centre for Medicines Discovery, Oxford, UK.
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.
Insights
Module 42 (M42) proteins, linked to Alzheimer's disease (AD), impact immune cell function. Midkine (MDK) and TMEFF2 ectodomain altered phagocytosis and calcium signaling, suggesting a role in AD immunity beyond amyloid pathology.
Area of Science:
- Neuroscience
- Immunology
- Proteomics
Background:
- A novel protein network, Module 42 (M42), was identified in post-mortem human brains and is strongly correlated with Alzheimer's disease (AD) pathology.
- M42 consists of 32 transmembrane and extracellular matrix proteins, including amyloid precursor protein (APP) and apolipoprotein E (apoE), implicated in amyloid beta (Aβ) pathology.
Purpose of the Study:
- To systematically evaluate the Aβ-independent effects of M42 proteins on immune cell function in vitro.
- To investigate the specific roles of M42 components in modulating immune responses relevant to AD.
Main Methods:
- Recombinant M42 proteins were expressed and purified.
- Human induced pluripotent stem cell-derived macrophages were treated with M42 proteins.
- Assays assessed phagocytosis, intracellular calcium (Ca2+) signaling, and cell viability.
Main Results:
- Midkine (MDK) reduced phagocytosis, while the ectodomain of Transmembrane protein with EGF-like and two follistatin-like domains 2 (TMEFF2) increased it.
- Both MDK and TMEFF2 ectodomain promoted intracellular Ca2+ signaling.
- TMEFF2 ectodomain suppressed Syk kinase activity; no M42 proteins affected cell viability.
Conclusions:
- M42 proteins play a role in regulating immune functions independently of Aβ pathology.
- These findings suggest M42 contributes to AD pathogenesis through modulation of immune responses.
