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Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer’s disease‐like symptom and pathology progression through increased turnover of amyloid precursor protein machinery
Author(s) -
Pickering Andrew
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.044272
Subject(s) - proteasome , proteostasis , transgene , biology , genetically modified mouse , microbiology and biotechnology , neurodegeneration , frontotemporal dementia , protein turnover , neuroscience , disease , medicine , biochemistry , dementia , protein biosynthesis , gene
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.