Investigating Protein interactions in Alzheimer's Disease. (360G-Wellcome-083103_Z_07_Z)

Alzheimer's disease (AD) is the most common cause of dementia, it affects over 24.3 million people worldwide with 4.6 million new cases diagnosed each year [1]. Since the number of people suffering with AD is expected to double every 20 years [1], AD represents one of the most pressing health concerns in an aging population. There are currently no effective treatments for AD which makes insight into the mechanisms behind the disease of considerable interest. Accumulation of the small (39-43 residue) peptide amyloid beta (A~) causes AD. Though the source of the peptide, the amyloid precursor protein (APP), and the enzymes responsible for its cleavage are known, the reason for its production and particularly its accumulation in an age-dependent manner remains much of an enigma. Crucial to being able to solve this problem is knowing what effect interactions between the key players in AD and other proteins have on the disease. This project aims to identify and characterise how protein interactions with APP and the ?-secretase BACE1 (which cleaves APP to generate A?) affect the production of A?. This will involve the investigation of potential interactions with the leucine rich repeat transmembrane 3 (LRRTM3) protein, F-Spondin and apolipoprotein E receptor 2 (ApoEr2). Specific objectives What is the role of LRRTM3 in the regulation of BACE1? Does LRRTM3 interact with BACE1 to alter BACE1 activity? Does LRRTM3 alter the cellular trafficking of BACE 1? Does the expression of LRRTM3 alter in AD and/or in aging? What role do ApoEr2 and F-Spondin play in the regulation of APP processing? What effect does the interaction of APP with F-Spondin and full length human ApoEr2 have on the production of AJ3? What are the molecular and cellular mechanisms underlying these effects? What is the effect of receptor activation on the ApoEr2, F-Spondin, APP complex and its ability to alter APP processing? Can any of these interactions be exploited as potential therapeutic strategies for AD? Can small molecules be used to interfere.with (or mimic) potential interaction sites on either APP or BACE1?