| Project Detail |
Alzheimer’s disease (AD) is an age-associated, irreversible neurodegenerative disorder. ? fundamental neuropathological hallmark of this disease is the accumulation of the amyloid-beta (Aß) peptide in the extracellular space and its aggregation in the brain. Interestingly, critical role for a healthy brain is played by clearance mechanisms of endothelial cells, which traverse the ?ß peptide through the Blood Brain Barrier (BBB), a highly selective semipermeable border. Studies in recent years have shown that endothelial cells remove Aß by endocytosis, and that impairment of this function is key to AD progression. However, the exact contribution of the distinct individual endocytic routes, as well as the involved molecular mechanisms, are largely unexplored. Hence, the main objective of ClearPath is to undertake a holistic approach that will shed light into the unexplored endocytic routes involved in brain Aß clearance and to identify the relationship between endocytic abnormalities and clinical pathologies of AD. To this end, ClearPath aims to: a. develop an in vitro co-culture BBB model system using endothelial and neuronal cells derived from established isogenic hiPSCs; b. screen the distinct endocytic routes to identify their contribution in Aß clearance; c. undertake bioinformatic analysis of genome-wide datasets from AD patients, to reveal novel disease-associated genes implicated in the endocytic routes; d. use transgenic animal models to validate the role of endocytic pathways in ?ß clearance. The multidisciplinary nature of this project warrants accomplishment of the research objectives, as well as advancement of the research capacity of the Post-doctoral fellow, thus boosting her career in the field. Besides, the results of the study will improve our understanding in Aß clearance mechanisms, thus contributing to novel strategies aiming to reduce the load of Aß peptide in the brain, thereby preventing or delaying the onset of the disease. |
