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Decreased hippocampal cell proliferation in mice with experimental antiphospholipid syndrome

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Abstract

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies, which may trigger vascular thrombosis with consecutive infarcts. However, cognitive dysfunctions representing one of the most commonest neuropsychiatric symptoms are frequently present despite the absence of any ischemic brain lesions. Data on the structural and functional basis of the neuropsychiatric symptoms are sparse. To examine the effect of APS on hippocampal neurogenesis and on white matter, we induced experimental APS (eAPS) in adult female Balb/C mice by immunization with β2-glycoprotein 1. To investigate cell proliferation in the dentate gyrus granular cell layer (DG GCL), eAPS and control mice (n = 5, each) were injected with 5-bromo-2′-deoxyuridine (BrdU) once a day for 10 subsequent days. Sixteen weeks after immunization, eAPS resulted in a significant reduction of BrdU-positive cells in the DG GCL compared to control animals. However, double staining with doublecortin and NeuN revealed a largely preserved neurogenesis. Ultrastructural analysis of corpus callosum (CC) axons in eAPS (n = 6) and control mice (n = 7) revealed no significant changes in CC axon diameter or g-ratio. In conclusion, decreased cellular proliferation in the hippocampus of eAPS mice indicates a limited regenerative potential and may represent one neuropathological substrate of cognitive changes in APS while evidence for alterations of white matter integrity is lacking.

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Abbreviations

aCL:

Anti-cardiolipin antibodies

aPL:

Antiphospholipid antibodies

APS:

Antiphospholipid syndrome

BBB:

Blood–brain barrier

BrdU:

5-Bromo-2′-deoxyuridine

BSA:

Bovine serum albumin

CA:

Cornu ammonis

CNS:

Central nervous system

CC:

Corpus callosum

CFA:

Complete Freund’s adjuvant

DCX:

Doublecortin

DG GCL:

Dentate gyrus granular cell layer

EAE:

Experimental autoimmune encephalomyelitis

eAPS:

Experimental antiphospholipid syndrome

LPS:

Lipopolysaccharide

NGS:

Normal goat serum

OD:

Optical density

PBS:

Phosphate buffered saline

PFA:

Paraformaldehyde

RT:

Room temperature

SEM:

Standard error of mean

SLE:

Systemic lupus erythematosus

SSC:

Saline-sodium citrate

TBS:

Tris-buffered saline

TBS-T:

TBS with Triton X-100

WM:

White matter

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Acknowledgements

The technical expertise of Magdeleine Herkt and Nicole Roder is kindly acknowledged. The authors are grateful to Professor Elisabeth Jane Rushing (University Hospital Zurich, Switzerland) for critically reading the manuscript.

Funding

The present work was supported by grants from the MAIFOR program (intramural funding, Medical Center of the Johannes Gutenberg University Mainz, Germany) from the Chief Scientist in the Israel Ministry of Health and from Israel Science Foundation. Katrin Frauenknecht is the recipient of a Career Development Award by the Stavros Niarchos Foundation (https://www.snf.org/22474).

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Author notes

  1. Katrin Frauenknecht

    Present address: Institute of Neuropathology, University Hospital of Zurich, University of Zurich, Schmelzbergstr. 12, 8091, Zurich, Switzerland

  2. Katrin Frauenknecht and Petra Leukel contributed equally.

Authors and Affiliations

  1. Institute of Neuropathology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    Katrin Frauenknecht, Petra Leukel, Harald D. von Pein & Clemens J. Sommer

  2. Department of Neurology, Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer, Israel

    Ronen Weiss, Aviva Katzav & Joab Chapman

  3. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    Ronen Weiss

  4. Focus Program Translational Neurosciences (FTN), Rhine Main Neuroscience Network (rmn2), Mainz, Germany

    Clemens J. Sommer

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  1. Katrin Frauenknecht
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Contributions

Experimental design: KF, AK, CJS; animal experiments: AK, RW; histology/volumetry/morphometric studies: KF, PL, HDP; figures: KF, PL, HDP; manuscript KF, PL, JC, CJS. All authors read and approved the final manuscript. The authors declare no competing interests.

Corresponding author

Correspondence to Katrin Frauenknecht.

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Ethical approval

Animal experiments have been approved Israeli Health Ministry (Ethical approval no. 775/12) and by the Chaim Sheba Medical Center Animal Welfare Committee. All experiments were in accordance with national and international guidelines and regulations. This article does not contain any studies with human participants performed by any of the authors.

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Frauenknecht, K., Leukel, P., Weiss, R. et al. Decreased hippocampal cell proliferation in mice with experimental antiphospholipid syndrome. Brain Struct Funct 223, 3463–3471 (2018). https://doi.org/10.1007/s00429-018-1699-9

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  • DOI: https://doi.org/10.1007/s00429-018-1699-9

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