Development of a 3D in vitro model mimicking the changes occurring at the blood-brain barrier during Alzheimer’s disease

A striking challenge in diagnosis and therapy of neurodegenerative diseases is the design of drugs able to cross the blood-brain barrier (BBB). In vitro BBB models are available, but they mimic only healthy conditions without taking into account the BBB alterations identified in neurodegenerative diseases, such as Alzheimer’s disease (AD). Therefore, NAB3 Project (funded by H2020 ERA-NET Co-fund JPND Programme) aims to develop and fully characterize a complex in vitro model of the AD-like BBB by combining different modified cellular models with both neuronal and organotypic brain slice cultures. NAB3 aims at both (i) manipulating/engineering the BBB in order to mimic the disease state as well as (ii) modulating ‘brain’-side towards a disease-like state in order to analyze its influence on the integrity of the BBB. NAB3 plans a three steps approach: 1) starting from present knowledge of the BBB alterations, these changes will be reproduced by drug-mediated manipulation (e.g. up- or down-regulation of metabolic pathways) and/or genetically engineering (e.g. over-expression of candidate genes or gene-silencing by RNA interference). 2) The project will further increase the knowledge on the disease-related changes occurring at the BBB by performing a transcriptomic and proteomic analysis on brain capillaries isolated from normal and Braak-staged brains. 3) The ‘brain’-side will be manipulated/engineered (e.g. increasing beta-amyloid production or using organotypic brain slices) in order to analyze the influence of the emerging pathology on the integrity of the BBB. The designed AD-like BBB model may allow to better design diagnostic and therapeutic tools in the pre-clinical phase.