{"database":"panorama","file_versions":[],"scores":null,"additional":{"omics_type":["Proteomics"],"submitter":["Laura Fichter"],"species":["Homo Sapiens"],"full_dataset_link":["https://panoramaweb.org/Qr5Ik5.url"],"submitter_email":["l-fichter@chu-montpellier.fr"],"submitter_affiliation":["PPC-LBPC, Université de Montpellier, INM INSERM, IRMB CHU de Montpellier, Montpellier, France"],"sample_protocol":[""],"repository":["PanoramaPublic"],"data_protocol":[""],"pubmed_abstract":["<h4>Background</h4>Tauopathies are neurodegenerative diseases all characterized by tau lesions in the brain. Nevertheless, a clinical and pathophysiological heterogeneity is present among them. This includes the dominant tau isoform found within aggregates (3R and/or 4R tau) along with different brain regions being affected. For some tauopathies, especially in Alzheimer's disease, a specific spatio-temporal staging of tau lesions is present. This staging has been the basis for the prion-like propagation hypothesis, which describes a cell-to-cell transfer of pathological tau species resulting in new aggregates formation in recipient neurons. Human extracellular vesicles isolated from the brain-derived fluid (BD-EVs) of Alzheimer's disease patients contain seeds that contribute to this tau pathology spreading. However, the nature of these tau species responsible for this nucleation activity remains unknown. Additionally, heterogeneity in seeding activity of BD-EVs of Alzheimer's disease, progressive supranuclear palsy and Pick's disease patients is known.<h4>Methods</h4>Here, EVs were isolated from human frozen tissue (Alzheimer's disease, Progressive Supranuclear Palsy, Pick disease and non-demented controls). We used a tau immunoprecipitation followed by high-resolution mass spectrometry to define their proteomic profile and test their seeding capacity in vitro.<h4>Results</h4>We show that the tau profile present within BD-EVs is different among tauopathies. Interestingly, multiple tau peptides located in the microtubule binding region were specifically enriched in Alzheimer's disease extracellular vesicles. Of these, mainly the PHF6 (VQIVYK) containing proteins mediate tau seeding activity.<h4>Conclusions</h4>PHF6 is a driver for the higher EVs-mediated tau propagation in AD patients, revealing an interesting therapeutic target to prevent tau pathology spreading."],"pubmed_title":["Tau profiling of brain extracellular vesicles reveals PHF6 peptide as core for pathological tau seeding in Alzheimer's disease."],"pubmed_authors":["Oosterlynck Marie M, Fichter Laura L, Leroux Elodie E, Eddarkaoui Sabiha S, Bouillet Thomas T, Lefebvre Camille C, Nguyen Marine M, Maurage Claude-Alain CA, Accart Bertrand B, Dupré Elian E, Landrieu Isabelle I, Danis Clément C, Lehmann Sylvain S, Vialaret Jérôme J, Buée Luc L, Hirtz Christophe C, Colin Morvane M"],"additional_accession":[]},"is_claimable":false,"name":"Tau Profiling of Brain Extracellular Vesicles Reveals PHF6 Peptide as Core for Pathological Tau Seeding in Alzheimer's Disease","description":"EVs are bilipid spheres known for their role in cellular communication through transport of proteins, lipids, RNA and more. In the brain, EVs are directly released in the interstitial fluid surrounding neural cells and hence entitled brain-derived EVs (BD-EVs). Human BD-EVs of AD patients contain seed-competent tau. Further, we demonstrated a different tau seeding capacity of AD, PSP and PiD patients derived EVs. This reflects a heterogenous contribution of BD-EVs to tau seeding among tauopathies, with AD BD-EVs showing the highest seeding capacity. Here, we aim to identify and compare the tau proteoforms found within EVs of tauopathies to assess if this tau content lays at the base of the heterogeneity observed for EVs seeding among tauopathies. A tau immunoprecipitation followed by mass spectrometry analysis (tau IP-MS), performed on BD-EVs from non-demented controls or patients affected with different tauopathies, revealed detection of 22 tryptic tau peptides with two MTBR tryptic peptides enriched only in AD BD-EVs. Among them, the well-known pro-aggregative hexapeptide PHF6 (VQIVYK) was found. Importantly, we demonstrated that PHF6-containing tau proteins are strongly implied in the seeding capacity of AD BD-EVs. From this, we conclude that the PHF6 is a driver for the higher EVs-mediated tau propagation in AD patients, revealing an interesting therapeutic target to prevent tau pathology spreading.","dates":{"publication":"Sun Sep 06 00:00:00 GMT+01:00 2026"},"accession":"PXD067593","cross_references":{"TAXONOMY":["9606"],"pubmed":["42298542"]}}