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Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer’s-like pathology in mouse and fly APP overexpression models

2022; American Association for the Advancement of Science; Volume: 8; Issue: 23 Linguagem: Inglês

10.1126/sciadv.abk2252

2375-2548

E. Sandra Chocrón, Erin Munkácsy, Harper S. Kim, Przemysław Karpowicz, Nisi Jiang, Candice E. Van Skike, Nicholas DeRosa, Andy Banh, Juan Pablo Palavicini, Paweł Wityk, Leszek Kalinowski, Verónica Galván, Paweł A. Osmulski, Elżbieta Jankowska, Maria Gaczyńska, Andrew M. Pickering,

Genetics and Neurodevelopmental Disorders

The 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). We 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 20