The role of neutrophils in the pathogenesis of Alzheimer's disease

Alzheimer’s disease (AD) is an age-related, severe and progressive neurodegenerative disorder with unknown etiology. It affects 35 million people worldwide and leads to cognitive deterioration, due to neuronal loss in brain regions involved in learning and memory. The two main neuropathological hallmarks of AD are: extracellular deposits (plaques) of amyloid-beta peptide (Aβ) and filamentous intracellular aggregates (neurofibrillary tangles) of hyperphophorylated tau protein. Recent data suggest that neuroinflammation may represent a new hallmark of disease and a potential driving force in AD. However, the inflammation mechanisms involved in AD pathogenesis remain largely unknown and a better understanding of the role of inflammation in AD may help to develop new therapeutic approaches to slow the progression of this disorder. The present study examined the role of vascular inflammation and leukocytes trafficking, in particular the role of neutrophils, in murine AD models and how these cells related to behavioral impairments and neuropathology. Confocal microscopy studies showed a progressive increase in the expression of ICAM-1, VCAM-1, E- and P-selectin and high numbers of inflammatory cells in the brain of in 5XFAD and 3xTg-AD mouse models of AD during early phase of disease when animals start to present cognitive deficit in behavioral tests. Surprisingly, we found that a large part of the infiltrating leukocytes were neutrophils, suggesting that these cells may play a role in disease pathogenesis. Moreover, confocal microscopy studies revealed that neutrophils produce neutrophil extracellular traps (NETs), suggesting that NET formation may represent a new disease mechanism in AD. Two-photon microscopy experiments confirmed the ability of neutrophils to efficiently invade the cortex and diffuse in high numbers in the parenchyma being potentially harmful to neural cells. Interestingly, soluble amyloid-beta 1-42 oligomers were able to trigger rapid integrin-dependent adhesion to human fibrinogen and ICAM-1 and LFA-1 affinity in neutrophils. Notably, neutrophil depletion as well as the blockade of neutrophil trafficking by anti-LFA-1 integrin antibody during early phase of disease, led to the inhibition of cognitive deficits in 5XFAD and 3xTg-AD mouse models, suggesting that neutrophils have a key role in brain damage and cognitive deficit in AD-like disease. Moreover, we found that inhibition of neutrophil function strongly reduced microglial activation and amyloid deposition, suggesting that neutrophils play a key role in disease progression. We also evaluated human cortical brain samples from subjects with AD and observed elevated numbers of neutrophils adhered and spread inside brain venules and migrated in the parenchyma and produced NETs compared to control subjects, indicating a possible role for these cells in humans as well. In conclusion, our results suggest that, starting at the early stage of AD, there is an active inflammatory process, which includes up-regulation of adhesion molecules on cerebrovascular endothelium and leukocyte trans-endothelial migration into the brain, particularly neutrophil recruitment. This further promotes vascular damage and neural cell dysfunction, contributing to cognitive deficits and AD progression. Therefore, neutrophils may play a pivotal role in the AD pathology and inhibition of neutrophil trafficking may represent a novel potential therapeutic target in AD.