The experimental antiphospholipid syndrome: an invaluable tool to study autoimmunity-induced neurodegeneration

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by high titers of auto-antibodies against phospholipids leading to thrombosis and consecutive infarcts. Many patients develop neurological symptoms in the absence of ischemia but the underlying mechanisms leading to these manifestations are not yet identified. In experimental APS (eAPS) mice with high aPL serum levels consistently develop behavioral abnormalities despite lack of ischemic brain injury. Therefore, it seems to be a valuable model to study principle mechanisms. In previous experiments we could link alterations of hippocampal neurotransmitter receptor binding densities to altered behavior. The present study was designed to identify possible underlying structural alterations of hippocampal neurons. Adult female Balb/C mice (n = 28) were subjected to either induction of eAPS (n = 14) by immunization with beta2-Glycoprotein 1 emulsified in Freund's adjuvant (CFA) or to a control group (n = 14) by immunization with CFA alone. Sixteen weeks post immunization mice were behaviorally tested in the staircase and Y-maze alternation test, serum autoantibody levels were determined and mice were then sacrificed. Golgi–Cox staining was used to analyze hippocampal neurons, dendrites and dendritic spines (n = 7/group). Immunohistochemistry was performed with antibodies against microtubule-associated protein 2 (MAP2), synaptobrevin 2 and synaptopodin, representing molecular markers of total dendritic integrity, presynaptic plasticity and dendritic spines (n = 7/group). eAPS resulted in increased aPL titers, abnormal behavior and impaired short term memory. This was further accompanied by reduced dendritic complexity of hippocampal CA1 neurons in the Golgi–Cox analysis as reflected by decreased dendritic length, arborization and spine density, respectively. Further the spine-associated protein expression of synaptopodin was reduced. In conclusion, our results are the first to indicate a role for the dendrites and in particular the dendritic spines in the pathogenesis of aPL-mediated central nervous system dysfunction in eAPS. The autoimmune-induced neurodegeneration in the absence of ischemia could also be a possible contributing factor to the central nervous system dysfunction in APS patients.