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Pharmacological intervention in a transgenic mouse model improves Alzheimer's-associated pathological phenotype: Involvement of proteasome activation.

Free radical biology & medicine (2020-12-07)
Aleksandra N Mladenovic Djordjevic, Marianna Kapetanou, Natasa Loncarevic-Vasiljkovic, Smilja Todorovic, Sofia Athanasopoulou, Milena Jovic, Milica Prvulovic, Era Taoufik, Rebecca Matsas, Selma Kanazir, Efstathios S Gonos
ABSTRACT

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by a progressive decline in a variety of cognitive and non-cognitive functions. The amyloid beta protein cascade hypothesis places the formation of amyloid beta protein aggregates on the first position in the complex pathological cascade leading to neurodegeneration, and therefore AD might be considered to be a protein-misfolding disease. The Ubiquitin Proteasome System (UPS), being the primary protein degradation mechanism with a fundamental role in the maintenance of proteostasis, has been identified as a putative therapeutic target to delay and/or to decelerate the progression of neurodegenerative disorders that are characterized by accumulated/aggregated proteins. The purpose of this study was to test if the activation of proteasome in vivo can alleviate AD pathology. Specifically by using two compounds with complementary modes of proteasome activation and documented antioxidant and redox regulating properties in the 5xFAD transgenic mice model of AD, we ameliorated a number of AD related deficits. Shortly after proteasome activation we detected significantly reduced amyloid-beta load correlated with improved motor functions, reduced anxiety and frailty level. Essentially, to our knowledge this is the first report to demonstrate a dual activation of the proteasome and its downstream effects. In conclusion, these findings open up new directions for future therapeutic potential of proteasome-mediated proteolysis enhancement.

MATERIALS
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Product Description

Sigma-Aldrich
Poly-L-lysine hydrobromide, mol wt 30,000-70,000, lyophilized powder, γ-irradiated, BioXtra, suitable for cell culture
Sigma-Aldrich
OxyBlot Protein Oxidation Detection Kit, The OxyBlot Protein Oxidation Detection Kit provides the reagents to perform the immunoblot detection of carbonyl groups introduced into proteins by oxidative reactions with ozone or oxides of nitrogen or by metal catalyzed oxidation.