Neutrophils induce Alzheimer’s disease-like pathology and cognitive decline via a mechanism dependent on LFA-1 integrin

International Congress on Neuroimmunology and Therapeutics

DoubleTree by Hilton Hotel San Francisco Airport, San Francisco, CA, USA

Gabriela Constantin

Posters-Accepted Abstracts: J Neurol Disord

Abstract :

Inflammation is a pathological hallmark of Alzheimerâ??s disease and understanding the underlying mechanisms may facilitate the development of new treatments. Using mice with five familial Alzheimerâ??s disease (5xFAD) mutations presenting amyloid pathology, and 3xTgâ??AD mice with both amyloid and tau pathology, we found increased expression of vascular adhesion molecules and increased accumulation of neutrophils in the brain. Neutrophils extravasated in areas with amyloid beta (Abeta) deposits, releasing neutrophil extracellular traps (NETs) and producing IL-17. Abeta1â??42 peptide triggered the LFA-1 integrin high-affinity state and rapid neutrophil adhesion. Two-photon laser-scanning microscopy experiments showed that LFA-1 integrin controls neutrophil extravasation and intraparenchymal motility. Neutrophil depletion or the inhibition of neutrophil trafficking using LFA-1 genetic ablation or an anti-LFA-1 antibody dramatically rescued memory loss in 5xFAD and 3xTg-AD mice. Interfering with neutrophil activity also reduced microglial density and activation, amyloid deposition, tau phosphorylation and restored synaptic protein loss. Importantly, restoration of cognitive function in mice with temporary inhibition of neutrophil function during early disease was maintained also at later time points in aged animals. To understand the relevance of our data in humans, we analyzed human cortical brain samples from subjects with Alzheimerâ??s disease. Our results showed that neutrophils adhered and spread inside brain venules or migrated into the parenchyma in high numbers and release NETs in Alzheimerâ??s brains compared to control subjects. In conclusion, our data demonstrate that neutrophils induce cognitive impairment and neuropathological changes suggesting that the inhibition of neutrophil trafficking may represent a new therapeutic strategy to address Alzheimerâ??s disease.