Development of an APP-specific B-secretase inhibitor for Alzheimer’s disease therapy

Developments of disease-modifying therapeutics that can slow or ultimately halt disease progression are urgently needed for treating Alzheimer’s disease (AD). Till date all anti-amyloid measures to treat AD have failed. This is often construed as amyloid being the wrong target but most of the amyloid-reducing approaches including targeting the amyloid producing enzymes have side effects. An attempt to develop a specific therapy with minimum mechanism-based side effects is proposed here. AD is characterized by the deposition of the b-amyloid (Ab) peptides, the production of which is initiated by β-Secretase (β-site APP cleaving enzyme 1; BACE1). Hence it is a prime target for AD therapy. Full or partial deletion of BACE1, although prevent the development of AD-like pathologies and memory impairments in different lines of APP transgenic mice, is also associated with specific behavioral and physiological alterations in mice, which are likely to be caused by failure in the physiological processing of various substrates. Hence, general inhibition of BACE1 might be associated with mechanism-based side effects as BACE1 mediates its various physiological functions through the processing of different substrates. An APP-specific BACE1 inhibitor has the potential to specifically inhibit Aβ production without the inhibition of the processing of other substrates. Hence, studying the biology of these substrates, examination of their structural, molecular and biochemical properties is essential for designing a BACE1 modulator. In this work, we propose to study the BACE1 cleavages of three newly identified substrates, namely: Neuregulin, Neural cell adhesion molecules CHL1 and L1. Biochemical, structural and cell biological examinations of the substrates will be performed to determine the affinity, cleavage efficiency, subcellular site of their beta-cleavage and sorting determinants. Our preliminary analysis of NRG1 cleavage suggests that BACE1 binds NRG1 with higher affinity  and cleaves it with a higher catalytic efficiency  than APP. As a result, BACE1 processing of NRG1 probably occurs in the biosynthetic compartment similar to the processing of the Swedish mutant of APP. Consistently, inhibition of endocytosis did not affect Neuregulin cleavage but did that of APP. This suggests that there are two pools of BACE1 in the cell: one the endosomal pool of BACE1 responsible for APP cleavage and the other non-endosomal pool cleaving high-affinity substrates such as NRG1. Exploiting this observation, we would like to check if endosomally targeted BACE1 inhibitors or anti-BACE1 ectodomain antibodies can specifically inhibit endosomal BACE1 cleavage of APP and thus spare those of NRG1, CHL1 and L1. Such therapies will reduce amyloid burden without much side effects from BACE1 inhibition.