image: (A, B) ALP staining and activity detection were performed after treating cells with APPswe or BMP2 for 5 days or 7 days. (C, D) ARS staining and semiquantitative analysis were used to detect calcium nodule formation after cells were treated with APPswe or BMP2 for 21 days. (E) The mRNA expression levels of genes related to osteogenic differentiation were measured by quantitative real-time PCR after cells were treated with APPswe or BMP2 for 48 h. (F) Western blot analysis was performed to detect the expression levels of osteogenic differentiation-related proteins after cells were treated with APPswe or BMP2 for 48 h. (G) The expression levels of the osteogenic differentiation proteins p-Smad1/5/8 and OCN in the different treatment groups were detected by cell immunofluorescence. MSCs were treated with APPswe for 24 h and then with BMP2 for 48 h to detect the expression of related proteins or mRNAs. n = 3; ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. APPswe, Swedish mutant amyloid precursor protein; MSC, mesenchymal stem cell; ALP, alkaline phosphatase; BMP2, bone morphogenetic protein 2; OCN, osteocalcin.
Credit: Genes & Diseases
Alzheimer's disease (AD), a chronic age-related neurodegenerative disease, currently affects 10% of adults aged 65 and older. While the amyloid precursor protein (APP), especially Swedish mutant APP (APPswe), is recognized as a significant pathogenic protein in AD, its effect on the skeletal system and underlying mechanisms remain poorly understood.
This research published in the Genes & Diseases journal by a team from Chongqing Medical University and Chengdu University analyzed the effects of APPswe and its intracellular and extracellular segments on the osteogenic differentiation of bone morphogenetic protein 2 (BMP2)-induced mesenchymal stem cells (MSCs).
Using the Gene Expression Omnibus (GEO) database, the researchers determined that APP was positively correlated with the osteogenic differentiation of MSCs but negatively correlated with their proliferation and migration. Notably, APPswe promoted BMP2-induced osteogenic differentiation of MSCs, while APPswe-C (APPswe without an intracellular segment) had the opposite effect. These findings imply that the intracellular domain of APPswe plays a vital role in promoting osteogenesis.
In vitro studies revealed that the intracellular domain of APPswe inhibited the activity of the Notch pathway by regulating the expression and nuclear translocation of NICD (Notch intracellular domain) through AICD (intracellular domain of APPswe) to promote the osteogenic differentiation of MSCs. Conversely, NICD overexpression reversed the ability of APPswe to promote the osteogenic differentiation of MSCs. Furthermore, APPswe-treated primary rat bone marrow MSCs exhibited the most favorable bone repair effect when a Gelatin methacryloyl (GelMA) hydrogel loaded with BMP2 was used for in vivo experiments, while APPswe-C had the opposite effect.
In summary, this study demonstrates that APPswe promotes the osteogenic differentiation of MSCs by regulating the Notch pathway. However, its extracellular segment blocks the self-renewal, proliferation, and migration of MSCs, resulting in the gradual depletion of MSC storage and affecting long-term bone formation. Overall, the findings of this research provide a theoretical basis for the early diagnosis and treatment of bone loss in AD patients, as well as the enhancement of fracture repair capabilities in AD patients.
Reference
Title of Original Paper: The bidirectional effects of APPswe on the osteogenic differentiation of MSCs in bone homeostasis by regulating Notch signalling
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2024.101317
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