Neurodegenerative diseases are progressive degenerative conditions characterized by the functional deterioration and ultimate loss of neurons. These incurable and debilitating diseases affect millions of people worldwide, and therefore represent a major global health challenge with severe implications for individuals and society. Recently, several neuroprotective drugs have failed in human clinical trials despite promising pre-clinical data, suggesting that conventional cell cultures and animal models cannot precisely replicate human pathophysiology. To bridge the gap between animal and human studies, three-dimensional cell culture models have been developed from human or animal cells, allowing the effects of new therapies to be predicted more accurately by closely replicating some aspects of the brain environment, mimicking neuronal and glial cell interactions, and incorporating the effects of blood flow. In this review, we discuss the relative merits of different cerebral models, from traditional cell cultures to the latest high-throughput three-dimensional systems. We discuss their advantages and disadvantages as well as their potential to investigate the complex mechanisms of human neurodegenerative diseases. We focus on in vitro models of the most frequent age-related neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease and prion disease, and on multiple sclerosis, a chronic inflammatory neurodegenerative disease affecting young adults.

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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.