Neuropathology of Experimental Antiphospholipid Syndrome (eAPS)

Antibodies against phospholipids and phospholipid binding proteins (aPL) have been identified as the major drivers of clotting in the vascular system in antiphospholipid syndrome (APS). Clotting results in the ischemic damage of organs, including the central nervous system (CNS). Interestingly, APS patients also show CNS dysfunction that cannot always be attributed to ischemic events. Manifestations such as cognitive dysfunction, depression, epilepsy, and white matter abnormalities are emerging and have an impact on the quality of life. So far, the underlying mechanisms are unknown and thus, specific treatment strategies are lacking. The four publications presented herein aim to investigate an experimental animal model of APS (eAPS), where female mice develop antiphospholipid antibodies (aPL) and behavioral and cognitive abnormalities, but show no overt signs of ischemic tissue damage. In summary, eAPS mice display a mild neurodegenerative phenotype without major tissue damage but rather subtle changes including hippocampal dysfunction, hippocampal neurotransmitter receptor changes, reduction of dendritic complexity of CA1 neurons, and decreased regenerative potential in the granule cell layer of the dentate gyrus. We conclude from these results that the hippocampus seems to be the major target in eAPS. The full spectrum of changes is seen only after prolonged exposure to high titers of aPL, which indicates that a critical threshold of aPL has to be reached to lead to the disease phenotype. The experimental data further indicate an antibody/immune-mediated CNS pathology, which possibly could be controlled by treatment strategies that result in a reduction of circulating aPL in the vascular system. Such strategies may diminish the risk or even protect APS patients from developing CNS manifestations