Antibody-based inhibition and functional studies of BACE1, the Beta-secretase in Alzheimer's disease

Alzheimer disease (AD) is the most common neurodegenerative disorder in the elderly population. Evidence suggests that accumulation of amyloid-β (Aβ) peptide as insoluble amyloid plaques plays a central role in the pathogenesis of AD. β-Secretase (BACE1) cleaves amyloid precursor protein (APP) and initiates the pathway for Aβ generation, it has been a prime drug target for AD intervention. Numerous efforts have been contributed to the rational design of inhibitor drug for BACE1, however, the progress has been challenged due to the large and unaccommodating nature of BACE1 active site, and the need to develop blood brain barrier (BBB)penetrating drug with high potency and high selectivity  against other aspartic proteases. This project aims to develop monoclonal antibody inhibitors as alternative approach for BACE1 inhibition. The features of monoclonal antibodies such as high affinity, high selectivity, and distinct structure and function domains amenable to protein engineering for therapeutic delivery, make them potential drug candidates. This project also aims to develop Nanobody
inhibitors for BACE1. Nanobodies are minimal sized antibodies, with superior properties for intracellular function including solubility, stability, and functionality without the requirement for association between heavy and light chains of conventional single chain variable fragments. Given the difficulties in the developing effective BBB-penetrating inhibitor drug for BACE1, we propose that gene delivery of Nanobody against BACE1 activity as novel approach for AD intervention. 

Keywords:Amyloid beta peptide

Disciplines:Genetics, Systems biology, Molecular and cell biology

Project type:PhD project