天美传媒

Abstract

One of the hallmarks of Alzheimer锟絪 disease is the formation of extracellular senile plaques, preferentially composed of Amyloid beta protein. Processing of Amyloid precursor protein leads to the production of two reservoirs of A尾: a secreted pool and a non-secreted cytoplasmic pool. Secreted A尾 contributes to extracellular plaques but despite various studies, the role of cytoplasmic A尾 in AD pathogenesis remains unclear. Indeed, the degree to which A尾 penetrates from vesicles through to the cytoplasm is not clear, however, it is likely that there is a dynamic equilibrium between all these pools. In this study, we hypothesise that cytoplasmic A尾 contributes to the toxicity of secreted A尾 through specific transmembrane interactions in our fly model of AD. Our preliminary experiments show that expression of aggregation prone form of extracellular A尾 leads to a reduction in longevity, locomotor deficits and the deposition of plaques while that of cytoplasmic A尾, on the other hand, is non-toxic. Interestingly, the co-expression of cytoplasmic A尾 enhances the plaque deposition and toxicity of extracellular A尾. To investigate how extracellular and cytoplasmic A尾 may interact we undertook an RNAi modifier screen of 115 candidate genes in Drosophila. We measured the increase in longevity caused by RNAi in flies expressing extracellular and cytoplasmic A尾. Only those RNAi constructs that did not also cause increased longevity in control flies (those expressing only extracellular A尾 and those not expressing A尾) were retained. By doing so, thirteen genes are found to specifically rescue the combined toxicity of cytoplasmic with extracellular A尾. Flottilin-1 and ABCB8 (CG1356) are the best validated modifiers that we have detected. The longevity data is also supported by brain histology, gene and protein expression measurements. Obtained results suggest a synergistic interaction between two pools of A尾 and highlight the importance of transmembrane A尾 interactions in AD pathology.

Biography

Mayida Azhar is a 3rd year PhD student in department of Genetics, University of Cambridge.