Behavioral and cognitive deficits occur only after prolonged exposure of mice to antiphospholipid antibodies

Abstract

The antiphospholipid (Hughes) syndrome (APS) includes systemic and central nervous system (CNS) pathology associated with antibodies to a complex of phospholipids and β₂-glycoprotein I (β₂-GPI). β₂-GPI immunized mice develop systemic manifestations of APS and we presently examined CNS manifestations in this APS model. Female BALB/c mice were immunized once with β₂-GPI in complete Freund's adjuvant (CFA) or with CFA alone (controls). A staircase test and a T-maze alternation test were performed to test behavior and cognition in independent groups of mice 6, 12 and 18 weeks following the immunization. The APS mice developed elevated levels of antibodies against negatively charged phospholipids and β₂-GPI. Neurological impairment was detected only 18 weeks after the induction of the APS and consisted of both cognitive (53± 4 71± 3% correct choices in the T-maze alternation for APS behavioral changes (higher number of rears (18± 2 vs 7±1, P < 0.02). This is the first report of cognitive deficits in this APS model and demonstrates the time course for the development of previously described behavioral changes. The mechanism involved in these CNS manifestations remains to be elucidated.

Keywords

antiphospholipid syndrome animal model behavior β2-glycoprotein I memory

Get full access to this article

View all access options for this article.

References

Hughes GRV . The antiphospholipid syndrome: ten years on . Lancet 1993; 342: 341–344 .

Petri M . Pathogenesis and treatment of the antiphospholipid antibody syndrome . Med Clin N Am 1997; 81: 151–177 .

Brey RL , Escalante A . Neurological manifestations of antiphospholipid antibody syndrome . Lupus 1998; 7: S67–S74 .

Mosek A , Yust I , Treves TA et al. Dementia and antiphospholipid antibodies . Dement Geriatr Cogn Disord 2000; 11: 36–38 .

Inzelberg R , Bornstein NM , Reider I , Korczyn AD . The lupus antic-oagulant and dementia in non-SLE patients . Dementia 1992; 3: 140–145 .

Roubey RA , Hoffman M . From antiphospholipid syndrome to anti-body-mediated thrombosis . Lancet 1997; 350: 1491–1493 .

Caronti B , Pittoni V , Palladini G , Valesini G . Anti-beta 2-glycoprotein I antibodies bind to central nervous system . J Neurol Sci 1998; 156: 211–219 .

Chapman J , Cohen-Armon M , Shoenfeld Y , Korczyn AD . Antiphospholipid antibodies permeabilize and depolarize brain synaptoneurosomes . Lupus 1999; 8: 127–133 .

Smith HR , Hansen CL , Rose R , Canoso RT . Autoimmune MRL-lpr/lpr mice are an animal model for the secondary antiphospholipid syndrome . J Rheumatol 1990; 17: 911–915 .

10.

Hess DC , Taormina M , Thompson J et al. Cognitive and neurologic deficits in the MRL/lpr mouse: a clinicopathologic study . J Rheumatol 1993; 20: 610–617 .

11.

Brey RL , Cote S , Barohn R et al. Model for the neuromuscular complications of systemic lupus erythematosus . Lupus 1995; 4: 209–212 .

12.

Ziporen L , Shoenfeld Y , Levy Y , Korczyn AD . Neurological dysfunction and hyperactive behavior associated with antiphospholipid antibodies. A mouse model . J Clin Invest 1997; 100: 613–619 .

13.

Galli M , Comfurius P , Maassen C et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor . Lancet 1990; 335: 1544–1547 .

14.

McNeil HP , Simpson RJ , Chesterman CN , Krilis SA . Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H) . Proc Natl Acad Sci USA 1990; 87: 4120–4124 .

15.

Gharavi AE , Sammaritano LR , Wen J , Elkon KB . Induction of antiphospholipid autoantibodies by immunization with β2 glycoprotein I (apolipoprotein H) . J Clin Invest 1992; 90: 1105–1109 .

16.

Blank M , Faden D , Tincani A et al. Immunization with antic-ardiolipin cofactor (beta-2-glycoprotein I) induces experimental antiphospholipid syndrome in naive mice . J Autoimmun 1994; 7: 441–455 .

17.

Garcia CO , Kanbour-Shakir A , Tang H et al. Induction of experimental antiphospholipid antibody syndrome in PL/J mice following immunization with beta 2 GPI . Am J Reprod Immunol 1997; 37: 118–124 .

18.

Brey RL , Cote SA , Teale JM . Autoimmune disease is accelerated in MRL/++ mice after apolipoprotein-H immunization . Neurology 1994; 44(Suppl 2): A316-A316 .

19.

Katzav A , Pick CG , Korczyn AD et al. Hyperactivity in a mouse model of the antiphospholipid syndrome . Lupus 2001; 10: 496–499 .

20.

Aron AL , Cuellar ML , Brey RL et al. Early onset of autoimmunity in MRL/++ mice following immunization with beta 2 glycoprotein I . Clin Exp Immunol 1995; 101: 78–81 .

21.

Polz E , Wurm H , Kostner GM . Investigations on beta 2-glycoprotein-I in the rat: isolation from serum and demonstration in lipoprotein density fractions . Int J Biochem 1980; 11: 265–270 .

22.

Bakimer R , Fishman P , Blank M et al. Induction of primary antiphospholipid syndrome in mice by immunization with a human monoclonal anticardiolipin antibody (H-3) . J Clin Invest 1992; 89: 1558–1563 .

23.

Simiand J , Keane PE , Morre M . The staircase test in mice: a simple and efficient procedure for primary screening of anxiolytic agents . Psychopharmacology 1984; 84: 48–53 .

24.

Pick CG , Peter Y , Terkel J , Gavish M , Weizman R . Effect of the neuroactive steroid alpha-THDOC on staircase test behavior in mice . Psychopharmacology 1996; 128: 61–66 .

25.

Ordy JM , Schjeide OA . Univariate and multivariate models for evaluating long-term changes in neurobiological development, maturity and aging . Prog Brain Res 1973; 40: 25–51 .

26.

Schrott LM , Crnic LS . Anxiety behavior, exploratory behavior, and activity in NZB £ NZW F1 hybrid mice: role of genotype and autoimmune disease progression . Brain Behav Immun 1996; 10: 260–274 .

27.

Sakic B , Szechtman H , Keffer M et al. A behavioral profile of auto-immune lupus-prone MRL mice . Brain Behav Immun 1992; 6: 265–285 .

28.

Sakic B , Szechtman H , Denburg JA . Neurobehavioral alterations in autoimmune mice . Neurosci Biobehav Rev 1997; 21: 327–340 .

29.

Gray JA , McNaughton N . Comparison between the behavioural effects of septal and hippocampal lesions: a review . Neurosci Biobehav Rev 1983; 7: 119–188 .

30.

Farr SA , Flood JF , Morley JE . The effect of cholinergic, GABAergic, serotonergic, and glutamatergic receptor modulation on posttrial memory processing in the hippocampus . Neurobiol Learn Mem 2000; 73: 150–167 .

31.

Romanides AJ , Duffy P , Kalivas PW . Glutamatergic and dopaminergic afferents to the prefrontal cortex regulate spatial working memory in rats . Neuroscience 1999; 92: 97–106 .

32.

Shavit S , Chapman J , Abukatash M et al. Dementia in the primary antiphospholipid syndrome (PAPS) is associated with increased age, high levels of antiphospholipid antibodies and diffuse brain pathology . Neurology 1993; 43(Suppl 2): A256-A256 .