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A striking challenge in diagnosis and therapy of neurodegenerative diseases is the design of drugs able to cross the blood-brain barrier (BBB), a tightly regulated barrier which prevents the passage of 98% of potential neuropharmaceuticals. In turn, the BBB may also hamper either early diagnosis and treatment monitoring of disease states. In vitro cellular BBB models are available, but they mimic only healthy conditions without taking into account the BBB alterations associated with neurodegenerative diseases. This proposal takes into account that these BBB alterations may be involved in the pathogenesis and progression of Alzheimer’s disease (AD) and that they may be also a consequence of the disease state. Moreover, this proposal considers that disease-related alterations of the BBB can interfere with the assessment of drug properties and therapeutic approaches in preclinical tests. Therefore, we aim to develop and characterize a complex in vitro model of the AD-like BBB, built up with different cellular types (endothelial cells, astrocytes, pericytes) combined with organotypic brain slices or neuronal cultures. The components of the model will be engineered to reproduce the disease changes and will be assembled in a transwell system, arranged in two physically separated compartments, representing the blood (upper compartment) and the brain (bottom compartment).

The project aims at both (i) manipulating/engineering the BBB in order to mimic the disease state, and (ii) modulating the ‘brain’-side towards a disease-like state, in order to analyze its influence on the BBB features. A three-step approach will be achieved thanks to the multidisciplinarity of the Consortium: 1) starting from the present knowledge of changes occurring at the BBB during AD, we will reproduce these changes by manipulation of metabolic pathways and/or genetic engineering (e.g. over-expression of candidate genes or gene-silencing by RNA interference). Effects of these manipulations will be tested and validated using molecules with already known permeability with respect to the normal BBB. 2) We will further increase our knowledge on the disease-related changes occurring at the BBB by performing transcriptomic and proteomic analysis on brain capillaries isolated from normal and Braak-staged human brains. These results (as well as new outcomes from the scientific community) will be utilized to further improve the model. 3) We will manipulate/engineer the ‘brain’-side (e.g. increasing ß-amyloid production or Tau phosphorylation) in order to analyze the influence of the emerging pathology on the BBB. The newly designed AD-like BBB model will provide an innovative tool i) to obtain new information on the pathogenesis and pathophysiology of AD; ii) to conduct more advanced early drug development and pre- clinical studies; iii) to devise new diagnostic or therapeutic strategies.

 

The Dutch partner will contribute to establishment and analysis of the neuronal cells with AD-like properties.

 

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