Establishment of new detection methods for the discovery and development of novel ABCA1 and ABCA7 modulators as Alzheimer’s disease (AD) therapeutics and diagnostics

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AD is a barely manageable, uncurable neurodegenerative disorder that poses a huge financial and emotional burden to western society. Insoluble cerebral amyloid-β (Aβ) proteins are both pathologically and diagnostically considered as the most important biomarker in AD, leading to neuronal cell death and clinical symptoms. While the initial causes of Aβ aggregation are yet unknown, pathological changes in (over)production, degradation, and clearance of Aβ proteins have been proposed. It has been well established within then last approximately 20 years that several ABC transporters are key players in Aβ distribution and clearance over the blood-brain-barrier (BBB). Amongst this protein superfamily, the ABCA subclass is most pronounced in AD pathology. Especially defects in the Abca1 and Abca7 genes – leading to less or un-functional ABCA1 and ABCA7 – showed statistically a higher risk to develop AD as revealed by genetic variant and genome-wide association studies. As these transporters do not directly transport Aβ proteins, it is believed that their impact on AD development and progression is associated with their ability to influence cellular cholesterol as well as phospholipid distribution, and thus, membrane constitution, composition, and fluidity. Especially their (intracellular) organization in lipid rafts and vesicular compartments are considered to impact all aspects of Aβ persistence – namely production, degradation, and clearance.Unfortunately, in contrast to other well-studied ABC transporter subclasses, directly interacting small-molecule modulators of ABCA transporters – although known for over 20 years – have barely been reported. In fact, only 12 compounds are known to inhibit ABCA1, while nothing is known regarding ABCA7. This can mainly be attributed to the lack of short-term high- throughput-screening (HTS) assays for the discovery of novel lead structures. However, inhibitors and activators of ABCA1 and ABCA7 would not only contribute to our understanding of the mechanistic aspects of these transporters, but may also be used as diagnostic tools and templates for the development of novel AD therapeutics. The study will focus on the development of novel detection methodologies to monitor ABCA1 and ABCA7 function, specifically tracing direct transport and ATPase activity. These assays will be used for both, the screening of large compound libraries to discover novel lead molecules for subsequent AD therapeutics and diagnostics development, and for the development of a computational model including basic scaffold and pattern analysis for screening of virtual compound libraries to extend the fund of known modulators of ABCA1 and ABCA7.