Ube3a deficiency inhibits amyloid plaque formation in APPswe/PS1δE9 mouse model of Alzheimer’s disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in memory and cognitive function. Pathological hallmark of AD includes aberrant aggregation of amyloid beta (Aβ) peptide, which is produced upon sequential cleavage of amyloid precursor protein (APP) by β- and γ -secretases. On the contrary, α-secretase cleaves APP within the Aβ sequence and thereby prevents Aβ generation. Here, we investigated the role of ubiquitin ligase Ube3a (involved in synaptic function and plasticity) in the pathogenesis of AD using APPswe/PS1δE9 transgenic mouse model and first noticed that soluble pool of Ube3a was age dependently decreased in AD mouse in comparison with wild type controls.  To further explore the role of Ube3a in AD patho-mechanism, we generated brain Ube3a-deficient AD mice that exhibited accelerated cognitive and motor deficits compared to AD mice. Interestingly, these Ube3a-deficient AD mice were excessively obese from their age of 12 months and having shorter lifespan. Biochemical analysis revealed that the Ube3a-deficient AD mice had significantly reduced level of Aβ generation and amyloid plaque formation in their brain compared to age-matched AD mice and this effect could be due to the increased activity of α-secretase, ADAM10 (a disintegrin and metalloproteinase-10) that shift the proteolysis of APP towards non-amyloidogenic pathway. These findings suggest that aberrant function of Ube3a could influence the progression of AD and restoring normal level of Ube3a might be beneficial for AD

Efficient Inhibition of Protein Aggregation, Disintegration of Aggregates, and Lowering of Cytotoxicity by Green Tea Polyphenol-Based Self-Assembled Polymer Nanoparticles

Green tea polyphenol epigallocatechin-3-gallate (EGCG) is known for its antiamyloidogenic property, and it is observed that molecular EGCG binds with amyloid structure, redirects fibrillation kinetics, remodels mature fibril, and lowers the amyloid-derived toxicity. However, this unique property of EGCG is difficult to utilize because of their poor chemical stability and substandard bioavailability. Here we report a nanoparticle form of EGCG of 25 nm size (nano-EGCG) which is 10–100 times more efficient than molecular EGCG in inhibiting protein aggregation, disintegrating mature protein aggregates, and lowering amyloidogenic cytotoxicity. The most attractive advantage of nano-EGCG is that it efficiently protects neuronal cells from the toxic effect of extracellular amyloid beta or intracellular mutant huntingtin protein aggregates by preventing their aggregation. We found that the better performance of nano-EGCG is due to the combined effect of increased chemical stability of EGCG against degradation, stronger binding with protein aggregates, and efficient entry into the cell for interaction with aggregated protein structure. This result indicates that the nanoparticle form of antiamyloidogenic molecules can be more powerful in prevention and curing of protein aggregation derived diseases