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

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.

Healthspan improvement and anti-aggregation effects induced by a marine-derived structural proteasome activator

“…Likewise, proteasome activation through a triterpene, namely 18α-glycyrrhetinic acid (18α-GA), conferred resistance to Aβ-induced proteotoxicity in various AD nematode models, as well as to murine cortical neurons exogenously supplemented with enhanced concentrations of Aβ peptide [ 17 ]. Similar positive results have also been observed for other natural compounds in various AD models [ 24 , 25 ].…”

Integrated Analysis of Weighted Gene Coexpression Network Analysis Identifying Six Genes as Novel Biomarkers for Alzheimer’s Disease

“…Moreover, the results of KEGG pathway analysis mainly highlighted categories such as "pathways of neurodegeneration-multiple diseases," "Alzheimer disease," "oxidative phosphorylation," and "proteasome." For example, the proteasome and its downstream effects have a dual effect on AD symptoms [25]. Proteasomes can degrade Aβ, thereby improving AD [26,27].…”

“…GO enrichment analysis demonstrated that the module with a strong positive correlation with AD participated in biological processes associated with mitochondria, including mitochondrial translation, mitochondrial gene expression, mitochondrial inner membrane, mitochondrial protein complex, NADH dehydrogenase activity, and oxidoreductase activity, acting on NAD (P)H.Mitochondrial dysfunction and oxidative stress may contribute to promoting the accumulation of amyloid- β peptides (A β ) and enhancing the phosphorylation levels of Tau [ 24 ]. Moreover, the results of KEGG pathway analysis mainly highlighted categories such as “pathways of neurodegeneration-multiple diseases,” “Alzheimer disease,” “oxidative phosphorylation,” and “proteasome.” For example, the proteasome and its downstream effects have a dual effect on AD symptoms [ 25 ]. Proteasomes can degrade A β , thereby improving AD [ 26 , 27 ].…”

Transcriptional regulatory networks of the proteasome in mammalian systems

“…Treatment of the animals with the Nrf2 activator 18a‐GA in combination with a structural proteasome activator (n‐3 fatty acids) enhanced proteasome activity and expression to ameliorate several AD‐related deficits. Specifically, this elevated proteolytic capacity in the cortex and hippocampus resulted in significant beneficial effects on body weight, motor function, cognitive abilities, anxiety, frailty level, and decreased Aβ42 coverage in both the parietal cortex and hippocampus of the 5xFAD mice 44 . In conclusion, these findings open up new directions for the future therapeutic potential of proteasome‐mediated proteolysis enhancement.…”