Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline associated with the deposition of amyloid-beta (A beta) plaques, hyperphosphorylation of tau protein, and neuronal loss. Vascular inflammation and leukocyte trafficking may contribute to AD pathogenesis, and a better understanding of these inflammation mechanisms could therefore facilitate the development of new AD therapies. Here we show that T cells extravasate in the proximity of cerebral VCAM-1(+) vessels in 3xTg-AD transgenic mice, which develop both A beta and tau pathologies. The counter-ligand of VCAM-1-alpha 4 beta 1 integrin, also known as very late antigen-4 (VLA-4) - was more abundant on circulating CD4(+) T cells and was also expressed by a significant proportion of blood CD8(+) T cells and neutrophils in AD mice. Intravital microscopy of the brain microcirculation revealed that alpha 4 integrins control leukocyte-endothelial interactions in AD mice. Therapeutic targeting of VLA-4 using antibodies that specifically block alpha 4 integrins improved the memory of 3xTg-AD mice compared to an isotype control. These antibodies also reduced neuropathological hallmarks of AD, including microgliosis, A beta load and tau hyperphosphorylation. Our results demonstrate that alpha 4 integrin-dependent leukocyte trafficking promotes cognitive impairment and AD neuropathology, suggesting that the blockade of alpha 4 integrins may offer a new therapeutic strategy in AD.

Blockade of α4 integrins reduces leukocyte-endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer's disease

Pietronigro, Enrica;Zenaro, Elena;Bianca, Vittorina Della;Dusi, Silvia;TERRABUIO, ELEONORA;IANNOTO, GIULIA;Slanzi, Anna;Ghasemi, Somayehsadat;NAGARAJAN, Rajasekar;Piacentino, Gennj;Tosadori, Gabriele;Rossi, Barbara;Constantin, Gabriela
2019

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline associated with the deposition of amyloid-beta (A beta) plaques, hyperphosphorylation of tau protein, and neuronal loss. Vascular inflammation and leukocyte trafficking may contribute to AD pathogenesis, and a better understanding of these inflammation mechanisms could therefore facilitate the development of new AD therapies. Here we show that T cells extravasate in the proximity of cerebral VCAM-1(+) vessels in 3xTg-AD transgenic mice, which develop both A beta and tau pathologies. The counter-ligand of VCAM-1-alpha 4 beta 1 integrin, also known as very late antigen-4 (VLA-4) - was more abundant on circulating CD4(+) T cells and was also expressed by a significant proportion of blood CD8(+) T cells and neutrophils in AD mice. Intravital microscopy of the brain microcirculation revealed that alpha 4 integrins control leukocyte-endothelial interactions in AD mice. Therapeutic targeting of VLA-4 using antibodies that specifically block alpha 4 integrins improved the memory of 3xTg-AD mice compared to an isotype control. These antibodies also reduced neuropathological hallmarks of AD, including microgliosis, A beta load and tau hyperphosphorylation. Our results demonstrate that alpha 4 integrin-dependent leukocyte trafficking promotes cognitive impairment and AD neuropathology, suggesting that the blockade of alpha 4 integrins may offer a new therapeutic strategy in AD.
Chronic inflammation, Alzheimer's disease
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/1000335
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