Apolipoprotein E (apoE) is a 34 kDa protein that functions as a key transporter of cholesterol and phospholipids in both the brain and the periphery. In the brain, it is produced primarily by astrocytes, and plays an important role in neuronal repair, synaptogenesis, and clearance of neurotoxic amyloid β peptides. There are three main isoforms of apoE in humans: apoE2, apoE3, and apoE4, that show genotype dependent effect on age and risk for developing sporadic and late-onset forms of Alzheimer’s disease (AD). In fact, apoE4 shows the strongest known genetic association with sporadic and late-onset forms of AD. Despite the critical role of apoE in the brain, the underlying mechanisms that regulate apoE expression and secretion in the brain are not well understood. We sought to utilize pheynotypic screening to identify novel mechanisms that regulate astrocytic apoE secretion. Accordingly, we developed a robust phenotypic screening strategy to evaluate custom screening collections such as Pfizer’s chemogenomics library comprising more than 700 biological mechanisms. Aside from LXR and RXR agonists that have been previously shown to increase apoE secretion, we found that pan class I histone deacetylase (HDAC) inhibitors elevated astrocytic apoE levels both <i>in vitro</i> and <i>in vivo</i> in human apoE3 knock-in mice. By using a combination of chemical probes and siRNA targeting specific HDACs, we demonstrated that pan class I HDAC inhibition was required for enhancing astrocytic apoE levels. Interestingly, unlike the LXR and RXR agonists, the pan class I HDAC inhibitor mediated increase in apoE was not dependent on LXRα and LXRβ. This presentation will describe the phenotypic screening strategy, hit triage, and follow up efforts to establish mechanism of action.

Identifying novel mechanisms for regulating brain apolipoprotein E levels using phenotypic screens

251st National Meeting (2016)

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