| First Author | Pietronigro E | Year | 2019 |
| Journal | Sci Rep | Volume | 9 |
| Issue | 1 | Pages | 12055 |
| PubMed ID | 31427644 | Mgi Jnum | J:283838 |
| Mgi Id | MGI:6387841 | Doi | 10.1038/s41598-019-48538-x |
| Citation | Pietronigro E, et al. (2019) Blockade of alpha4 integrins reduces leukocyte-endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer's disease. Sci Rep 9(1):12055 |
| abstractText | Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline associated with the deposition of amyloid-beta (Abeta) 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 Abeta and tau pathologies. The counter-ligand of VCAM-1 - alpha4beta1 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 alpha4 integrins control leukocyte-endothelial interactions in AD mice. Therapeutic targeting of VLA-4 using antibodies that specifically block alpha4 integrins improved the memory of 3xTg-AD mice compared to an isotype control. These antibodies also reduced neuropathological hallmarks of AD, including microgliosis, Abeta load and tau hyperphosphorylation. Our results demonstrate that alpha4 integrin-dependent leukocyte trafficking promotes cognitive impairment and AD neuropathology, suggesting that the blockade of alpha4 integrins may offer a new therapeutic strategy in AD. |
