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Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline associated with the deposition of amyloid-β (Aβ) 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 Aβ and tau pathologies. The counter-ligand of VCAM-1 – α4β1 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 α4 integrins control leukocyte–endothelial interactions in AD mice. Therapeutic targeting of VLA-4 using antibodies that specifically block α4 integrins improved the memory of 3xTg-AD mice compared to an isotype control. These antibodies also reduced neuropathological hallmarks of AD, including microgliosis, Aβ load and tau hyperphosphorylation. Our results demonstrate that α4 integrin-dependent leukocyte trafficking promotes cognitive impairment and AD neuropathology, suggesting that the blockade of α4 integrins may offer a new therapeutic strategy in AD.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, affecting ~6% of the global population aged >65 years[1]
We found that neutrophils and T cells extravasated near VCAM-1+ cerebral vessels in 3xTg-AD mice, suggesting a role for this endothelial adhesion molecule in leukocyte migration into the brain during AD
VCAM-1 expression in the cerebral vessels of human AD patients has not been investigated, higher levels of soluble VCAM-1 are found in plasma samples from AD patients compared to controls, and the levels of soluble VCAM-1 correlate with more advanced dementia and changes in white matter hyper-intensity[22,23]
Summary
Alzheimer’s disease (AD) is the most common form of dementia, affecting ~6% of the global population aged >65 years[1]. Our recent data show that neutrophils (the most abundant leukocytes in the human circulation) adhere in cerebral vessels and migrate into the AD brain They migrate into the brain parenchyma of 3xTg-AD and 5xFAD mouse models of AD at the onset of memory deficit, secreting IL-17 and producing neutrophil extracellular traps (NETs) that may harm endothelial www.nature.com/scientificreports/. Targeting the α4 chain of VLA-4 has a therapeutic effect in patients with multiple sclerosis, a chronic inflammatory disease of the CNS, and in Chron’s disease, an autoimmune disease of the intestine, demonstrating that blocking key adhesion mechanisms controlling leukocyte migration can efficiently mitigate chronic inflammation in human diseases. We found that VLA-4 contributes to the inflammatory response in 3xTg-AD mice and could be targeted for AD therapy
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