Biology subjects

Ercan-Herbst, E.

Publications and source records attributed to Ercan-Herbst, E..

4 recordsLinked to original sources

bioRxiv2020

Tau in the brain interstitial fluid is fragmented and seeding-competent

In Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that in Tau transgenic mice, human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells. Notably, immunodepletion of ISF phosphorylated Tau, but not Tau fragments, significantly reduces its ability to seed Tau aggregation and only a fraction of Tau, separated by ultracentrifugation, is seeding competent. These results indicate that ISF seeding competence is driven by a small subset of Tau, which potentially contribute to the propagation of Tau pathology. HighlightsO_LIIn interstitial fluid (ISF) of transgenic mice, Tau comprises >10 distinct fragments C_LIO_LIISF Tau decreases with Tauopathy progression, while its phosphorylation increases C_LIO_LIOnly ISF from mice with established Tauopathy is seeding competent in vitro C_LIO_LIRemoval of phospho-Tau reduces ISF seeding competence C_LIO_LIISF seeding competence is driven by less soluble, aggregated and phosphorylated Tau C_LI Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗

bioRxiv2020

SETD7-mediated lysine monomethylation is abundant on non-hyperphosphorylated nuclear Tau

Human tauopathies including Alzheimers disease (AD) are characterized by alterations in the post-translational modification (PTM) pattern of Tau, leading to the formation of insoluble aggregates, neuronal dysfunction and degeneration. Using a mass spectrometry approach, we identified multiple sites of lysine monomethylation on Tau isolated from a detergent-soluble fraction of human brain, some of which were increased in early AD samples. Brain tissues derived from a mouse model of tauopathy demonstrate an age-dependent increase in methylation at specific sites, with methylated Tau enriched in the soluble nuclear fraction and not associated with hyperphosphorylated, insoluble Tau species. Furthermore, we show that the protein lysine methyltransferase SETD7 methylates Tau at K132 and demonstrate an interaction with K130, an additional methylation site in close vicinity. These findings shed light on the function of a novel type of PTM on Tau that provide a potential signal for its translocation to different subcellular sites. Since the mislocalization and depletion of Tau from axons is associated with tauopathies, our findings may furthermore provide insight into this disease-associated phenomenon.

neuroscience↗

bioRxiv2019

A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer’s disease brain

Tau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimers disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking. Here we apply a comprehensive electrochemiluminescence ELISA assay to analyze twenty-five different PTM sites as well as tau oligomerization in control and sporadic AD brain. The samples were classified as Braak stages 0-I, II or III-IV, respectively, corresponding to the progression of microscopically detectable tau pathology throughout different brain regions. We find that soluble tau oligomers are strongly increased at Braak stages III-IV in all brain regions under investigation, including the temporal cortex, which does not contain NFTs at this stage of pathology. We additionally identified five phosphorylation sites that are specifically and consistently increased across the entorhinal cortex, hippocampus and temporal cortex in the same donors. Three of these sites correlate with tau oligomerization in all three brain regions, but do not overlap with the epitopes of phospho-sensitive antibodies commonly used for the immunohistochemical detection of NFTs. Our results thus suggest that soluble oligomers are characterized by a small set of specific phosphorylation events that differ from those dominating in mature NFTs and shed light on early PTM changes of tau during AD pathogenesis in human brains.

neuroscience↗

bioRxiv2019

Asparagine endopeptidase cleaves tau at N167 after uptake into microglia

BackgroundTau cleavage by different proteolytic enzymes generates short, aggregation-prone fragments that have been implicated in the pathogenesis of Alzheimers disease (AD). Asparagine endopeptidase (AEP) activity in particular has been associated with tau dysfunction and aggregation, and the activity of the protease is increased in both aging and AD. Methods and ResultsUsing a mass spectrometry approach we identified a novel tau cleavage site at N167 and confirmed its processing by AEP. In combination with the previously known site at N368, we show that AEP cleavage yields a tau fragment that is present in both control and AD brains at similar levels. AEP is a lysosomal enzyme, and our data suggest that it is expressed in microglia rather than in neurons. Accordingly, we observe tau cleavage at N167 and N368 after endocytotic uptake into microglia, but not neurons. However, tau168-368 does not accumulate in microglia and we thus conclude that the fragment is part of a proteolytic cascade leading to tau degradation. ConclusionsWhile we confirm previous studies showing increased overall AEP activity in AD brains, our data suggests that AEP-mediated cleavage of tau is a physiological event occurring during microglial degradation of the secreted neuronal protein. The disease-associated increase in active AEP may thus be related to pro-inflammatory conditions in AD brains, and our findings argue against AEP inhibition as a therapeutic approach in AD.

neuroscience↗