Morphologic and Functional Effects of Gamma Secretase Inhibition on Splenic Marginal Zone B Cells
Open accessAbstract
The γ-secretase complex is a promising target in Alzheimer’s disease because of its role in the amyloidogenic processing of β-amyloid precursor protein. This enzyme also catalyzes the cleavage of Notch receptor, resulting in the nuclear translocation of intracellular Notch where it modulates gene transcription. Notch signaling is essential in cell fate decisions during embryogenesis, neuronal differentiation, hematopoiesis, and development of T and B cells, including splenic marginal zone (MZ) B cells. This B cell compartment participates in the early phases of the immune response to blood-borne bacteria and viruses. Chronic treatment with the oral γ-secretase inhibitor RO4929097 resulted in dose-dependent decreased cellularity (atrophy) of the MZ of rats and mice. Significant decreases in relative MZ B-cell numbers of RO4929097-treated animals were confirmed by flow cytometry. Numbers of MZ B cells reverted to normal after a sufficient RO4929097-free recovery period. Functional characterization of the immune response in relation to RO4929097-related MZ B cell decrease was assessed in mice vaccinated with inactivated vesicular stomatitis virus (VSV). Compared with the immunosuppressant cyclosporin A, RO4929097 caused only mild and reversible delayed early neutralizing IgM and IgG responses to VSV. Thus, the functional consequence of MZ B cell decrease on host defense is comparatively mild.
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Chronic inhibition of γ-secretase activity in rodents leads to reduced percentage of marginal zone B cells in the spleen.
“In addition, chronic inhibition of γ -secretase activity in rodents leads to reduced percentage of marginal zone B cells in the spleen [16].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [16]
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Research works printed but not linked: 19
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Richter, L. R., Wan, Q., Wen, D., Zhang, Y., Yu, J., Kang, J. K., Zhu, C., McKinnon, E. L., Gu, Z., Qiang, L., et al. (2020) · ACS Nano · doi:10.1021/acsnano.0c01007 · Cited by 59 · see citing works
Is there a role for B cells in Alzheimer's disease?
Charavner, E.-L., Fillatreau, S., & El Behi, M. (2026) · Cellular Immunology · doi:10.1016/j.cellimm.2026.105154
- Authors
- de Vera Mudry, M. C., Regenass-Lechner, F., Ozmen, L., Altmann, B., Festag, M., Singer, T., Müller, L., Jacobsen, H., & Flohr, A.
- Affiliations
- Non-Clinical Safety, Pharma Research and Early Development, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland
- F. Hoffmann-La Roche AG (CH)
- Venue
- International Journal of Alzheimer's Disease
- Publisher
- Wiley
- Published
- 2012
- Volume
- 2012
- Pages
- 1-7
- ISSN
- 2090-0252 (ISSN-L)
- 2090-8024
- PMC
- PMC3534238
- OpenAlex
- W2115406848
- Cited by
- 6
- References
- 0
- Citations by year
- 2023: 3 · 2020: 1 · 2019: 1 · 2018: 1
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- International Journal of Alzheimer s Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- gamma-secretase inhibition, RO4929097, Notch signaling, neutralizing antibody response, cyclosporine, Alzheimer's disease, host defense
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