Targeting leukocyte integrins has therapeutic effect in Alzheimer's-like disease

Vascular inflammation and a dysfunctional blood-brain-barrier have been implicated in the pathogenesis of Alzheimer's disease. However, the role of leukocyte trafficking mechanisms in Alzheimer's disease in the induction of neuropathological changes and memory deficit is unclear. We carried out two-photon laser-scanning microscopy (TPLSM) experiments in the brain of mice with five familial Alzheimer's disease (5xFAD) mutations presenting amyloid pathology, and 3xTgAD mice with both amyloid and tau pathology and observed that fluorescently labeled neutrophils and activated lymphocytes adhere to the vascular endothelium and migrate into the brain parenchyma in these animals. Blocking monoclonal antibodies to LFA-1 (alphaLbeta2) and VLA-4 (alpha4beta1) integrins significantly inhibited neutrophil and lymphocyte adhesion in brain vessels, suggesting that leukocyte integrins play a role in leukocyte extravasation in Alzheimer's disease models. In addition, our TPLSM data showed that leukocytes from LFA-1 deficient mice are completely unable to adhere or crawl in the blood vessels and thus to transmigrate in the brain parenchyma of Alzheimer's disease mice. LFA1 or VLA-4 inhibition using monoclonal antibodies clearly improved memory function compared to mice treated with a control antibody, restoring performance to levels comparable with wild-type age-matched littermates in Y maze and contextual fear conditioning tests. The role of LFA-1 integrin was confirmed by crossing 3xTg-AD animals with the LFA-1-deficient Itgal-/- strain. We found that the 3xTg-AD mice lacking LFA-1 integrin showed improved memory in cognitive tests compared to wild-type animals. These findings were supported by neuropathological data showing a lower density and activation state of microglia in 3xTg-AD mice deficient of LFA-1 integrin compared to 3xTg-AD aged-matched controls. We also found that the temporary LFA-1 blockade with an anti-LFA-1 antibody during the early stages of disease preserved the cognitive functions of the mice at later time points suggesting that therapeutic blockade of leukocyte adhesion during the early stages of disease provides a long-term beneficial effect on cognition in older mice. Current Alzheimer's disease therapies provide only temporary improvement and marginally reduce the rate of cognitive decline. Therefore, we propose that targeting integrins controlling leukocyte trafficking may represent a new therapeutic strategy in Alzheimer's disease.