Harnessing new targets and mechanisms mediating AD pathogenesis

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Alzheimer’s disease (AD) is an incurable neurodegenerative brain disorder that causes progressive memory loss and cognitive decline, and is the No.1 cause of dementia. It is characterized by the coexistence of extracellular amyloid plaques, mainly formed by the amyloid beta-42 (Abeta) peptide, and intracellular neurofibrillary tangles containing aggregates of abnormal tau. Abeta and tau were considered as disconnected culprits for many years, but in view of recent studies, it is clear that they are intimately related and possess synergistic activities. Sadly, very little is known about how Abeta and tau interactions trigger AD pathogenesis, which significantly hinders the development of effective treatments. To address this, we generated a new fly model of AD that genetically produces both human Abeta and tau resulting in synergistic pathology. These flies display extracellular deposits of thioflavin-S-positive Abeta, intracellular aggregation and phosphorylation of wild-type tau, and progressive loss of neuronal cells. The robust and consistent pathology of these flies provides a unique opportunity for gene discovery efforts and thus we performed a massive loss-of-function RNAi screen in the fly eye, which provides a useful and easy-to-score phenotype. Out of 6,600 RNAi stocks tested, we identified 31 suppressors and 119 enhancers, including multiple genes not previously known to be associated with AD. Most suppressors are linked to protein modification or cleavage, ribosomal function, cell metabolism, transcription, chromatin modulation, and transport to name a few. Here, we will employ a strategically designed pipeline that integrates genetics with high-throughput behavioral platforms and target prioritization to identify robust late-stage modifiers of the disease (Aim 1). On the other hand, we will fast-track a mechanistic and therapeutic analysis of one of the strongest suppressors along with its human homologue (Aim 2). This suppressor encodes a highly disordered protein of uncharacterized function and was also found in two other genetic screens performed by us. Thus, we have labelled it as a high-priority target. We strongly believe that manipulation of the 150 modifiers of Abeta+tau toxicity presented here will provide the foundation for new types of targets or therapeutics. Therefore, this work may contribute significantly to the goals of the National Plan to Address Alzheimer’s Disease.