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Antidepressant sertraline increases thioflavin-S and Congo red deposition in APPswe/PSEN1dE9 transgenic mice.

ABSTRACT: Introduction: Depression is strongly associated with Alzheimer's disease (AD). Antidepressants are commonly used in patients before and after their diagnosis of AD. To date, the relationship between antidepressants and AD remains unclear. Methods: In our study, we administered sertraline or paroxetine to wild type (WT) and APPswe/PSEN1dE9 (APP/PSEN1) transgenic mouse models for up to 12 months. We quantified the drug concentrations using LC-MS/MS analysis and measured serum serotonin level using an ELISA assay. Additionally, we evaluated the amyloid burdens through thioflavin-S and Congo red stainings, and recognition memory using the novel object recognition test. Results: Our findings revealed that mice treated with paroxetine exhibited a significantly higher level of weight gain compared to the control group and increased mortality in APP/PSEN1 mice. After 12 months of antidepressant treatment, the sertraline level was measured at 289.8 ng/g for cerebellum, while the paroxetine level was 792.9 ng/g for cerebellum. Sertraline significantly increased thioflavin-S and Congo red depositions, along with gliosis, in both isocortex and hippocampus of APP/PSEN1 mice compared to the control group. Both antidepressants also led to a decreased recognition index in APP/PSEN1 mice. Conclusion: These findings suggest a potential role of sertraline in AD pathogenesis, emphasizing the need to reassess the use of these antidepressants in patients with AD.

SUBMITTER: Liao MH

PROVIDER: S-EPMC10800414 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Antidepressant sertraline increases thioflavin-S and Congo red deposition in APPswe/PSEN1dE9 transgenic mice.

Liao Ming-Hsuan MH Lin Yen-Kuang YK Gau Fong-Ying FY Tseng Chun-Che CC Wu Da-Chih DC Hsu Chu-Yuan CY Chung Kuo-Hsuan KH Li Rung-Chi RC Hu Chaur-Jong CJ Then Chee Kin CK Shen Shing-Chuan SC

Frontiers in pharmacology 20240108

<b>Introduction:</b> Depression is strongly associated with Alzheimer's disease (AD). Antidepressants are commonly used in patients before and after their diagnosis of AD. To date, the relationship between antidepressants and AD remains unclear. <b>Methods:</b> In our study, we administered sertraline or paroxetine to wild type (WT) and APPswe/PSEN1dE9 (APP/PSEN1) transgenic mouse models for up to 12 months. We quantified the drug concentrations using LC-MS/MS analysis and measured serum seroton ...[more]

PMID: 38259283

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Project description:PurposePathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (A?) levels in the brain early in Alzheimer's disease (AD). The time course and relationships between astrocytosis and A? deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis.MethodsPET imaging with the amyloid plaque tracer (11)C-AZD2184 and the astroglial tracer (11)C-deuterium-L-deprenyl ((11)C-DED) was carried out in APPswe mice aged 6, 8-15 and 18-24 months (4-6 animals/group) and in wild-type (wt) mice aged 8-15 and 18-24 months (3-6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for A? deposition and astrocytosis by in vitro autoradiography using (3)H-AZD2184, (3)H-Pittsburgh compound B (PIB) and (3)H-L-deprenyl and immunostaining performed with antibodies for A?42 and glial fibrillary acidic protein (GFAP) in sagittal brain sections.Results(11)C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18-24 months than in age-matched wt mice. Cortical and hippocampal (11)C-DED PET binding was significantly higher at 6 months than at 8-15 months or 18-24 months in APPswe mice, and it was also higher than at 8-15 months in wt mice. In vitro autoradiography (3)H-AZD2184 and (3)H-PIB binding confirmed the in vivo findings with (11)C-AZD2184 and demonstrated age-dependent increases in A? deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in (3)H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more A?42 deposits in the cortex and hippocampus and more GFAP(+) reactive astrocytes in the hippocampus at 18-24 months than at 6 months in APPswe mice.ConclusionThe findings provide further in vivo evidence that astrocytosis occurs early in AD, preceding A? plaque deposition.

Project description:BackgroundAmyloid-β deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer's disease (AD). Dysregulation of the endosomal-autophagic-lysosomal (EAL) pathway, which impairs amyloid precursor protein processing, is one of the earliest changes in AD. However, the precise role of EAL pathway in neurodegeneration remains unclear. This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction.MethodsWe used 3-, 7-, and 12-month-old APPswe/PSEN1dE9 (APP/PS1) mice to model different stages of AD with age- and gender-matched wild-type littermates as controls (4-7 mice per group) and detected the changes of EAL markers, endosomal organizers Rab5 and Rab7, autophagosome marker LC3B, and lysosomal proteins Lamp1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis. To further explore the mechanism of EAL dysregulation in AD, components of the class III phosphatidylinositol 3-kinase (PI3KC3) complex, activators of Rab7 (Beclin1 and UVRAG), and the negative regulator of Rab7 (Rubicon) were also measured in this two brain regions.ResultsIn 7-month-old APP/PS1 brain that amyloid beta initiated to accumulate intracellularly, EAL pathway, and related PI3KC3 members, UVRAG and Beclin1 were upregulated both in cortex and hippocampus (all P < 0.05). By the age of 12 months old, when abundant amyloid plaques formed, EAL markers, UVRAG, and Beclin1 were also upregulated in the cortex (all P < 0.05). However, Rab7 was decreased significantly (P = 0.0447), accompanied by a reduction of its activating PI3KC complex component Beclin1 (P = 0.0215) and enhancement of its inhibiting component Rubicon (P = 0.0055) in the hippocampus.ConclusionsOur study implies that EAL pathway, represented as Rab7 and its PI3KC3 regulators' expressions, showed temporal and spatial variation in brains at different stages of AD. It provides new insights into the role of EAL pathway in pathogenesis and indicates potential therapeutic targets in neurodegenerative diseases.

Project description:Study questionDo selective serotonin reuptake inhibitor (SSRI) antidepressants affect the function of human sperm?Summary answerThe SSRI antidepressant Sertraline (e.g. Zoloft) inhibits the sperm-specific Ca2+ channel CatSper and affects human sperm function in vitro.What is known alreadyIn human sperm, CatSper translates changes of the chemical microenvironment into changes of the intracellular Ca2+ concentration ([Ca2+]i) and swimming behavior. CatSper is promiscuously activated by oviductal ligands, but also by synthetic chemicals that might disturb the fertilization process. It is well known that SSRIs have off-target actions on Ca2+, Na+ and K+ channels in somatic cells. Whether SSRIs affect the activity of CatSper is, however, unknown.Study design, size, durationWe studied the action of the seven drugs belonging to the most commonly prescribed class of antidepressants, SSRIs, on resting [Ca2+]i and Ca2+ influx via CatSper in human sperm. The SSRI Sertraline was selected for in-depth analysis of its action on steroid-, prostaglandin-, pH- and voltage-activation of human CatSper. Moreover, the action of Sertraline on sperm acrosomal exocytosis and penetration into viscous media was evaluated.Participants/materials, setting, methodsThe activity of CatSper was investigated in sperm of healthy volunteers, using kinetic Ca2+ fluorimetry and patch-clamp recordings. Acrosomal exocytosis was investigated using Pisum sativum agglutinin and image cytometry. Sperm penetration in viscous media was evaluated using the Kremer test.Main results and the role of chanceSeveral SSRIs affected [Ca2+]i and attenuated ligand-induced Ca2+ influx via CatSper. In particular, the SSRI Sertraline almost completely suppressed Ca2+ influx via CatSper. Remarkably, the drug was about four-fold more potent to suppress prostaglandin- versus steroid-induced Ca2+ influx. Sertraline also suppressed alkaline- and voltage-activation of CatSper, indicating that the drug directly inhibits the channel. Finally, Sertraline impaired ligand-induced acrosome reaction and sperm penetration into viscous media.Limitations, reasons for cautionThis is an in vitro study. Future studies have to assess the physiological relevance in vivo.Wider implications of the findingsThe off-target action of Sertraline on CatSper in human sperm might impair the fertilization process. In a research setting, Sertraline may be used to selectively inhibit prostaglandin-induced Ca2+ influx.Study funding/competing interest(s)This work was supported by the Swiss Centre for Applied Human Toxicology (SCAHT), the Département de l'Instruction Publique of the State of Geneva, the German Research Foundation (CRU326), the Interdisciplinary Center for Clinical Research, Münster (IZKF; Str/014/21), the Innovation Fund Denmark (grant numbers 14-2013-4) and the EDMaRC research grant from the Kirsten and Freddy Johansen's Foundation. The authors declare that no conflict of interest could be perceived as prejudicing the impartiality of the research reported.Trial registration numberNA.

Dataset Information

Antidepressant sertraline increases thioflavin-S and Congo red deposition in APPswe/PSEN1dE9 transgenic mice.

Publications

Antidepressant sertraline increases thioflavin-S and Congo red deposition in APPswe/PSEN1dE9 transgenic mice.

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