BLOCKADE OF ALPHA4 INTEGRINS AMELIORATES COGNITIVE DYSFUNCTION AND NEUROPATHOLOGICAL CHANGES IN TRANSGENIC ANIMALS WITH ALZHEIMER'S-LIKE DISEASE

Abstract

Blood-derived leukocyte subpopulations, including lymphocytes, monocytes and neutrophils, have been identified in the brains of patients with Alzheimer’s disease (AD) and in corresponding animal models, but their role in disease pathogenesis is unclear. We have recently demonstrated that neutrophils infiltrate the AD brain and that neutrophil depletion has therapeutic effect in AD transgenic mouse models. However, leukocyte trafficking mechanisms in the central nervous system (CNS) during AD are largely unknown and our goal was to determine the role of alpha4 integrins in disease pathogenesis. Intravital microscopy studies were performed to visualize and analyze leukocyte-vascular interactions in 3xTg-AD mice, which present both amyloid and tau pathology. Contextual fear conditioning and Y maze tests were performed to analyze the cognitive deficit. Neuropathological studies were performed to evaluate amyloid beta deposition, tau hyperphosphorylation, microglial activation and expression of synaptic proteins. Intravital microscopy studies performed in the CNS microcirculation of 3xTg-AD mice showed that blockade of alpha4 integrins prevents activated T cell rolling and firm adhesion on brain endothelium. Treating 3xTg-AD mice with an anti-alpha4 integrin antibody starting during early disease phases in mice already presenting cognitive deficits clearly improved memory function compared to mice treated with a control antibody in Y maze and contextual fear conditioning tests. These findings were supported by neuropathological data showing a reduction in Abeta deposition and lower density and activation state of microglia in the cortex and hippocampus of 3xTg-AD mice treated with anti-alpha4 antibody compared to animals treated with an isotype control antibody. Moreover, anti-apha4 treatment reduced tau hyperphosphorylation and restored synaptic protein expression compared to control animals. Notably, restoration of cognitive function in mice with temporary anti-alpha4 treatment during early disease was maintained also at later time points in aged animals, suggesting that therapeutic blockade of leukocyte adhesion during the early stages of disease provides a long-term beneficial effect on cognition in older mice. Antibodies anti-alpha4 integrin are currently used for the treatment of patients with autoimmune diseases and our data suggest that blockade of alpha4 integrins may represent a novel therapeutic approach in AD that has the potential for rapid translation into the clinic.