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Blockade of ?4 integrins reduces leukocyte-endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline associated with the deposition of amyloid-? (A?) 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? and tau pathologies. The counter-ligand of VCAM-1 - ?4?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 ?4 integrins control leukocyte-endothelial interactions in AD mice. Therapeutic targeting of VLA-4 using antibodies that specifically block ?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? load and tau hyperphosphorylation. Our results demonstrate that ?4 integrin-dependent leukocyte trafficking promotes cognitive impairment and AD neuropathology, suggesting that the blockade of ?4 integrins may offer a new therapeutic strategy in AD.

SUBMITTER: Pietronigro E

PROVIDER: S-EPMC6700124 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Pietronigro Enrica E Zenaro Elena E Bianca Vittorina Della VD Dusi Silvia S Terrabuio Eleonora E Iannoto Giulia G Slanzi Anna A Ghasemi Somayehsadat S Nagarajan Rajasekar R Piacentino Gennj G Tosadori Gabriele G Rossi Barbara B Constantin Gabriela G

Scientific reports 20190819 1

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<sup>+</sup> v ...[more]

PMID: 31427644

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Project description:Background. The blood-brain barrier (BBB) regulates immune cell entry into the CNS, and various strategies have been developed to target this barrier in efforts to alleviate neuroinflammation in neurodegenerative diseases. α4β1 is crucial for T cell influx into the CNS. In the context of HIV, CD4 T cells drive viral infiltration, while CD8 T cells are essential for viral clearance. This dual role complicates strategies aimed at targeting T cell entry during HIV infection, yet it remains an area that has not been thoroughly explored. Methods. We investigated the impact of disrupting α4-mediated T cell entry into the CNS in SIVmac251-infected rhesus macaques treated with an α4-blocking antibody (n=4) versus an isotype control (n=4). Our comprehensive approach included single-cell analysis of CD45+ cells in the brain and spleen, spatial transcriptomics of the hippocampus, viral load measurements, and flow cytometry on brain tissue. Results. Single-cell analysis revealed a marked reduction in the brain CD8 TEM cluster, particularly in cells expressing Granulysin, CCL5, and STAT4, while CD4 T cell clusters remained unchanged, and two monocyte clusters were enriched. This shift was accompanied by an increase in brain SIV RNA+ CD45+ CD4+ T cells in the α4-treated group (vRNA+ cells = 60) compared to controls (n=11). Spatial transcriptomics of SIV vRNA+ versus SIV vRNA- regions in the hippocampus of α4-treated macaques showed enrichment of CD4 TCM and monocyte gene signatures. Correspondingly, quantitative PCR revealed higher vRNA levels in the gray matter of the PFC, STS, and Hp. These findings suggest that α4 blockade selectively disrupts CD8 TEM populations while sparing CD4 T cells, leading to elevated viral loads and heightened neuroinflammation. The increase in SIV RNA+ CD4+ T cells and viral loads in the gray matter furthermore underscores the compartmentalized effect of α4-mediated immune modulation on viral dynamics across distinct brain regions Conclusion. These results underscore the critical need to evaluate immune-targeting therapies, with implications for strategies aimed at controlling T cell influx in the context of viral infections in the brain.

Dataset Information

Blockade of ?4 integrins reduces leukocyte-endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer's disease.

Publications

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

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