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Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer’s disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer’s disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain. Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer’s disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer’s disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain. ispartof: Nature vol:612 issue:7938 pages:123-131 ispartof: location:England status: published

The number of atomic-resolution structures of disease-associated amyloids has greatly increased in recent years. These structures have confirmed not only the polymorphic nature of amyloids but also the association of specific polymorphs to particular proteinopathies. These observations are strengthening the view that amyloid polymorphism is a marker for specific pathological subtypes (e.g. in tauopathies or synucleinopathies). The nature of this association and how it relates to the selective cellular vulnerability of amyloid nucleation, propagation and toxicity are still unclear. Here, we provide an overview of the mechanistic insights provided by recent patient-derived amyloid structures. We discuss the framework organisation of amyloid polymorphism and how heterotypic amyloid interactions with the physiological environment could modify the solubility and assembly of amyloidogenic proteins. We conclude by hypothesising how such interactions could contribute to selective cellular vulnerability.

Summary Amyloid polymorphism is emerging as a key property that is differentially linked to various conformational diseases, including major neurodegenerative disorders, but also as a feature that potentially relates to complex structural mechanisms mediating transmissibility barriers and selective vulnerability of amyloids. In response to the rapidly expanding number of amyloid fibril structures formed by full-length proteins, we here have developed StAmP-DB, a public database that supports the curation and cross-comparison of experimentally determined three-dimensional amyloid polymorph structures. Availability and implementation StAmP-DB is freely accessible for queries and downloads at https://stamp.switchlab.org.

Highly ordered, straight amyloid fibrils readily lend themselves to structure determination techniques and have therefore been extensively characterized. However, the less ordered curly fibrils remain relatively understudied, and the structural organization underlying their specific characteristics remains poorly understood. We found that the exemplary curly fibril-forming protein ovalbumin contains multiple aggregation prone regions (APRs) that form straight fibrils when isolated as peptides or when excised from the full-length protein through hydrolysis. In the context of the intact full-length protein, however, the regions separating the APRs facilitate curly fibril formation. In fact, a meta-analysis of previously reported curly fibril-forming proteins shows that their inter-APRs are significantly longer and more hydrophobic when compared to straight fibril-forming proteins, suggesting that they may cause strain in the amyloid state. Hence, inter-APRs driving curly fibril formation may not only apply to our model protein but rather constitute a more general mechanism.

Currently, all clinically used androgen receptor (AR) antagonists target the AR ligand-binding pocket and inhibit T and dihydrotestosterone (DHT) binding. Resistance to these inhibitors in prostate cancer frequently involves AR-dependent mechanisms resulting in a retained AR dependence of the tumor. More effective or alternative AR inhibitors are therefore required to limit progression in these resistant stages. Here, we applied the structural information of the ligand-binding domain (LBD) dimerization interface to screen in silico for inhibitors. A completely new binding site, the Dimerisation Inhibiting Molecules (DIM) pocket, was identified at the LBD dimerization interface. Selection of compounds that fit the DIM pocket via virtual screening identified the DIM20 family of compounds which inhibit AR transactivation and dimerization of the full-length AR as well as the isolated LBDs. Via biolayer interferometry, reversible dose-dependent binding to the LBD was confirmed. While DIM20 does not compete with 3H-DHT for binding in the LBP, it limits the maximal activity of the AR indicative of a noncompetitive binding to the LBD. DIM20 and DIM20.39 specifically inhibit proliferation of AR-positive prostate cancer cell lines, with only marginal effects on AR-negative cell lines such as HEK 293 and PC3. Moreover, combination treatment of DIM compounds with enzalutamide results in synergistic antiproliferative effects which underline the specific mechanism of action of the DIM compounds.

Anti-apoptotic Bcl-2-family members not only act at mitochondria but also at the endoplasmic reticulum, where they impact Ca

The present article reports on the career of Professor Nikolaos Louros and his contribution to the development of obstetrics and gynaecology. The data presented is based on desk research with the aim to gather and analyse relevant credible information from documents existing in primary and secondary resources in the archive of Foundation History of Medicine N. Louros. As a Professor at the University of Athens, Louros introduced new teaching methods. His multifaceted work includes writing, teaching, research, and the clinical and laboratory context. His scientific interest covers all areas of obstetrics and gynaecology. Pioneering and progressive in the medical field, he invented new clinical and surgical methods with international appeal. As a director, Louros established innovative rules in the Maternity Hospitals he directed. He supported every effort aiming to protect maternity and the child, and adopted a new approach regarding the problem of home based obstetric help to the destitute women.