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O2‐06‐04: Tau deletion triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment
Author(s) -
Sotiropoulos Ioannis,
Lopes Sofia,
Lopes Andre,
Guimaraes Marco,
Pinto Vitor,
Sardinha Vanessa M.,
Pinheiro Sara,
Oliveira Joao,
Sousa Nuno,
Leite-Almeida Hugo
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.07.162
Subject(s) - neuroscience , neuropathology , hyperphosphorylation , sciatic nerve , motor system , efferent , psychology , dementia , motor function , peripheral , tau protein , medicine , disease , pathology , alzheimer's disease , biology , physical medicine and rehabilitation , afferent , kinase , microbiology and biotechnology
Background: Trans-synaptic spread of tau pathology is AD is generally accepted but the process is poorly understood. We have recently reported that most synaptic tau is c-terminal truncated, and have also demonstrated depolarization-induced release of total tau from AD but not aged control synapses. Release of tau from synapses is a presumed major source of CSF tau, which is a core CSF biomarker for AD and other neurodegenerative diseases, including traumatic brain injury. The importance of extracellular tau is highlighted by a recent literature documenting success with tau immunotherapy; however a lack of clarity about the precise species of tau peptide that is released presents a significant barrier with respect to tau immunotherapeutic approaches. Methods: We examined the supernatants from depolarized synaptosomes to categorize the peptide species of tau and investigate release of exosomes in a series of normal and AD cases. Release experiments used cryopreserved synaptosomes prepared from samples with a post-mortem interval less than 12h; synaptosomes were depolarized in a 5 min incubation in Kreb’s Ringer buffer containing 50mM KCl. Results: In the present experiments, tau release supernatants were probed with an antibody directed against the intact C-terminus of tau, and demonstrated a 6-fold increase in release of intact C-terminal tau by depolarization in AD samples (79.25 vs. 494 RFU, p<0.002); no significant depolarization-induced release was observed in aged control synaptosomes. An antibody directed against caspase-cleaved tau (TauC3 antibody; D421) did not reveal differential release. Release of exosomes into tau release supernatants was probed with the exosome-associated protein Alix (PDCD61P), an auxillary ESCRT protein that supportes viral budding. Alix is detected as aw75 kDa protein in tau release supernatants, but shows only a trend for depolarization-induced release in the control samples. Conclusions: These results demonstrate robust depolarization-induced release of tau from cryopreserved postmortemAD synaptic terminals, and indicate release of multiple tau peptide species along with synaptic release of exosomal markers. Because C-terminal truncated tau is associated with increased aggregation, release of tau with an intact C terminal may follow from retention of fragmented tau in intraterminal aggregates.