Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer’s‐like pathology in animal models of AD

Abstract

AbstractBackgroundThe proteasome has key roles in neuronal proteostasis, including the removal of misfolded and oxidized proteins, presynaptic protein turnover, and synaptic efficacy and plasticity. Proteasome dysfunction is a prominent feature of Alzheimer’s disease (AD).MethodWe investigate proteasome augmentation through overexpression of a rate limiting proteasome subunit and treatment with proteasome activating peptidomimetics developed by our team in hAPP(J20) mice, MC65 cells overexpressing a C99 fragment of APP and elav‐GS‐GAL4>UAS‐APP;UAS‐BACE1 fly models of AD.ResultWe show that prevention of proteasome dysfunction by genetic manipulation delays mortality, cell death, and cognitive deficits in fly and cell culture AD models. We developed a transgenic mouse with neuronal‐specific proteasome overexpression that, when crossed with an AD mouse model, showed reduced mortality and cognitive deficits. To establish translational relevance, we developed a set of TAT‐based proteasome‐activating peptidomimetics that stably penetrated the blood‐brain barrier and enhanced 20S/26S proteasome activity. These agonists protected against cell death, cognitive decline, and mortality in cell culture, fly, and mouse AD models.ConclusionWe demonstrate proteasome modulation as a viable target for prevention of AD‐like deficits and present a set of novel proteasome agonists as AD therapeutics