Tau filaments are tethered within brain extracellular vesicles in Alzheimer's disease.

The abnormal assembly of tau protein in neurons is the pathological hallmark of multiple neurodegenerative diseases, including Alzheimer's disease (AD). In addition, assembled tau associates with extracellular vesicles (EVs) in the central nervous system of patients with AD, which is linked to its clearance and prion-like propagation between neurons. However, the identities of the assembled tau species and the EVs, as well as how they associate, are not known. Here, we combined quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy to study brain EVs from AD patients. We found filaments of truncated tau enclosed within EVs enriched in endo-lysosomal proteins. We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging. Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD.

Aging-related SUMOylation pattern in the cortex and blood plasma of wild type mice.

Protein activities and mechanisms related to aging has become a growing interest nowadays. Since SUMOylation is implicated in several cellular processes, its investigation related to senescence, aging and frailty is of high interest. In our study, wild type mice cortical lysates, synaptosomes and plasma have been processed to evaluate SUMOylation and SUMO machinery expression (Ubc9 and SENP1 enzymes) profile at different ages. In cortical lysates, SUMO-1ylation reached a peak at 6 months followed by a decrease; while in synaptosomes, it progressively increased till 18 months. Regarding SUMO-2/3ylation, it was observed a similar trend in both lysate and synaptosomes where the protein conjugation was the highest at 6 months but interestingly decreased afterwards. In addition, Ubc9 and SENP1 enzymes showed a linear increased expression level in both brain preparations. Since SUMOylation process is ubiquitously expressed, we were interested to identify SUMO conjugation at peripheral level too. Thus, SUMO-1ylation and SUMO-2/3ylation expression level has been detected in mouse plasma that revealed an inverted U-shaped curve trend during mice lifespan. Surprisingly, SENP1 enzyme was not present in the plasma while Ubc9 enzyme reached a plateau at 6 months and was highly expressed till 18 months. In conclusion, our data indicates that SUMOylation is highly correlated with age-related processes which indisputably need to be considered for further investigation.

An overview of the possible therapeutic role of SUMOylation in the treatment of Alzheimer's disease.

Nowadays, Alzheimer's disease (AD) is recognized as a multifactorial neurological pathology whose complexity is the cause of our still low achievements in the understanding of the associated mechanisms as well the discovery of a possible definitive cure. Clinicians are aware of the few possibilities offered by medicine to cure Alzheimer's patients, restore their memory and take them back to normal life. Unfortunately, the therapeutic tools available today are not able to contrast the pathology. In the last years the tendency of the research is to formulate new hypotheses that can help to develop future effective drugs. Here we propose an overview about an interesting intracellular mechanism called SUMOylation which belongs to the post-translational modification family. SUMOylation is currently studied from few decades and it has been observed to be implicated in the molecular mechanisms of several neurological disorders including AD. Interestingly, the unbalance between SUMOylation/deSUMOylation seems to be involved in the switch from physiological to pathological behaviours of several proteins implied into AD etiology. Nevertheless, there are no pharmacological treatments known to modulate SUMOylation/deSUMOylation equilibrium. We hereby listed some natural compounds that, due to their effects on this molecular mechanism, they deserve attention for inspire the development of future convincing therapies.