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

Tumor markers. Consensus Conference on Diagnosis and Prognostic Parameters in Localized Prostate Cancer. Stockholm, Sweden, May 12-13, 1993

This chapter mainly deals with biochemical aspects on prostate specific antigen (PSA) and its clinical value. To a limited extent, also other tumor markers, which might be of importance in the evaluation of patients with prostate cancer are discussed. In serum, PSA exists in a free form or bound to antichymotrypsin. Interestingly, only 10% of PSA secreted from cancer cells seems to exist in a free form, as compared to 30% of PSA secreted from cells in benign prostatic hyperplasia (BPH). PSA seems to be closely, but not absolutely, related to tumor grade and stage. The mean value of PSA in patients with tumors dominated by Gleason grades 3 or below, was 10 ng/ml, compared to 29 ng/ml in those with higher grades. Patients with PSA values of 50 ng/ml or above almost exclusively had tumor of Gleason grades 4 or 5, and this limit usually reflected a generalized disease. Patients with PSA-values below 10 ng/ml almost exclusively had tumors confined to the prostate gland. In countries where screening for prostate cancer is believed in, it is important to understand that normal cut-off values are related to patient's age. The upper normal limit of males below 50 years of age should be set at 2.5 ng/ml, as compared to 6.5 ng/ml for men over 70 years of age. To improve the value of PSA determination and for scientific purposes, the standardization of the assay is urgently needed and under way. Prostate acid phosphatase (PAP) has in most centres been replaced by PSA. An elevated PAP value, as measured by the enzymatic method, invariably indicates a generalized disease and could thus be used as a complementary informative assay to PSA. Other markers have been used mainly to achieve additional prognostic information. In a multivariate analysis, the non-specific tumor marker neopterin, which reflects the host response to tumor antigens, was closely related to short-term prognosis. Neopterin was followed by thymidine kinase, a protein reflecting the cell turn-over and tumor grade. Also PSA at diagnosis seemed to add some prognostic information, whereas other markers did not