Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer's disease‐like symptom and pathology progression through increased turnover of amyloid precursor protein machinery: Molecular and cell biology/protein clearance/recycling. (7th December 2020)

• Record Type: Journal Article
• Authors: Pickering, Andrew
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.044272
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: The proteasome has key roles in neuronal proteostasis, including removal of misfolded or oxidized proteins, presynaptic protein turnover, as well as synaptic efficacy and plasticity. Proteasome dysfunction is a prominent feature of Alzheimer's disease (AD). Artificial impairment of proteasome function can mimic many neurodegenerative phenotypes. Methods: We created transgenic mice and flies as well as novel proteasome activating drugs to examine whether proteasome augmentation can reduce AD like symptoms in animal models of the disease. Results: We report that manipulation of proteasome activity can influence the rate of AD‐like progression. We show that augmentation of proteasome function in fly and cell culture models of AD delays mortality, cell death, and AD‐like cognitive deficits. We developed a transgenic mouse with neuronal‐specific proteasome overexpression which, when crossed with a mouse model of AD, reduced mortality and diminished AD‐like cognitive deficits. To establish translational relevance, we developed a set of novel proteasome‐activating peptidomimetics based on modifications of proteasome binding fragments derived from the viral protein HIV‐1 Tat. These agonists stably penetrate the blood‐brain‐barrier and enhance 20S as well as 26S proteasome activity. We show that treatment with these agonists protects against cell death in a cell culture model of AD as well as both cognitive decline and mortality in fly and mouse models of AD. The protective effects observed from proteasome overexpression in our models appear to be driven at least in part by increased turnover of the amyloid precursor protein (APP) and β‐secretase enzyme (BACE1) by the proteasome. Conclusion: We conclude that the proteasome plays an important role in AD‐like progression. Furthermore augmentation of proteasome function is protective against AD‐like pathogenesis in diverse models of the disease, potentially representing a new therapeutic target for treatment of AD.