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

E. Sandra Chocron, Erin Munkácsy, Harper S. Kim, Przemyslaw Karpowicz, Nisi Jiang, Candice E. Van Skike, Nicholas DeRosa, Andy Q. Banh, Juan P. Palavicini, Paweł Wityk, Leszek Kalinowski, Veronica Galvan, Pawel A. Osmulski, Elzbieta Jankowska, Maria Gaczynska, Andrew M. Pickering

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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 20S/26S proteasome activity. These agonists protected against cell death, cognitive decline, and mortality in cell culture, fly, and mouse AD models. The protective effects of proteasome overexpression appear to be driven, at least in part, by the proteasome's increased turnover of the amyloid precursor protein along with the prevention of overall proteostatic dysfunction.

Original languageEnglish (US)
Pages (from-to)eabk2252
JournalScience Advances
Volume8
Issue number23
DOIs
StatePublished - Jun 10 2022

ASJC Scopus subject areas

  • General

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