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Serum amyloid P component (SAP) modulates antidepressant effects through promoting membrane insertion of the serotonin transporter

Abstract

Serum amyloid P component (SAP) is a universal constituent of human amyloid deposits including those in Alzheimer’s disease. SAP has been observed to be elevated in patients with depression, and higher SAP levels are associated with better response to the antidepressant escitalopram. The mechanisms underlying these clinical observations remain unclear. We examined the effect of SAP on serotonin transporter (SERT) expression and localization using Western blot, confocal microscopy, and positron emission tomography with the radioligand [11C]DASB. We also investigated the effect of SAP on treatment response to escitalopram in mice with the forced swim test (FST), a classical behaviour paradigm to assess antidepressant effects. SAP reduced [11C]DASB binding as an index of SERT levels, consistent with Western blots showing decreased total SAP protein because of increased protein degradation. In conjunction with the global decrease in SERT levels, SAP also promotes VAMP-2 mediated SERT membrane insertion. SAP levels are correlated with behavioural despair and SSRI treatment response in mice with FST. In MDD patients, the SAP and membrane SERT levels are correlated with response to SSRI treatment. SAP has complex effects on SERT levels and localization, thereby modulating the effect of SSRIs, which could partially explain clinical variability in antidepressant treatment response. These results add to our understanding of the mechanism for antidepressant drug action, and with further work could be of clinical utility.

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Fig. 1: Decreased [11C]DASB binding in brains of mice treated with SAP.
Fig. 2: SAP treatment regulates the total and membrane expression levels of SERT.
Fig. 3: SAP facilitates membrane insertion of SERT in a VAMP2-dependent manner in cortical neurons.
Fig. 4: SAP blocks SSRI-induced SERT internalization.
Fig. 5: SAP levels are correlated with behavioural despair and SSRI treatment response in mice, and the levels of SERT on the membrane of PBMCs from patients with MDD with escitalopram treatment.

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Funding

This work was supported by Advanced Innovation Center for Human Brain Protection, Capital Medical University, and Center for Addiction and Mental Health.

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FL oversaw and supervised the overall project. PS conducted the Western blot analysis of both mouse brain tissues, HEK293T cells, and human samples as well as measurement of SAP in human samples with help from QC and FJSL. SY carried out the experiments using confocal microscope. JY, ZS, JZ, and ML recruited the patients with MDD and collected the blood samples. JT, AJ, and DZ conducted the PET scanning with support from NV. FY JC, and YL performed the mouse FST experiments with help from ZX, and YL measured the mouse SAP levels. JS and PS analyzed the human data with help from XW. FL, AHCW, PS, SY, JT, and JS wrote the manuscript.

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Correspondence to Fang Liu.

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Su, P., Yan, S., Yang, J. et al. Serum amyloid P component (SAP) modulates antidepressant effects through promoting membrane insertion of the serotonin transporter. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01449-4

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