. Photodynamic studies reveal rapid formation and appreciable turnover of tau inclusions. Acta Neuropathol. 2021 Mar;141(3):359-381. Epub 2021 Jan 26 PubMed.

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  1. This paper by Dr. Cara Croft and colleagues is an elegant demonstration that fibrillar tau aggregates in neurons are not static structures in the organotypic brain slice model used. I was particularly interested that the half-life of inclusions was longer in longer-term cultures, which begs the questions, what is the turnover like in aged human brain? Is this difference a function of the age of the tissue or age of the inclusion?

    This paper is important as it lends hope that strategies to prevent tau aggregation may both prevent further aggregation and eventually lead to removal of existing aggregates due to this turnover. However, it is worth a note of caution that it is likely not the fibrillar aggregates that are toxic but rather soluble forms of tau, so we need a clearer understanding of which forms of tau are neurotoxic in order to develop effective therapeutic strategies.

    View all comments by Tara Spires-Jones
  2. Abundant filamentous tau inclusions are characteristic of a number of human neurodegenerative diseases, collectively referred to as tau proteinopathies. The presence of inclusions correlates with neurodegeneration and a causal connection became clear following the identification of mutations in MAPT that give rise to familial forms of frontotemporal dementia.

    Croft and colleagues showed previously that brain-slice cultures transduced with recombinant adeno-associated viruses that encode 0N4R P301L/S320F human tau develop inclusions and subsequent nerve cell death (Croft et al., 2019). Abundant tau filaments were present. In the new work, they now report that the inclusions are dynamic, with a half-life of approximately seven days (Croft et al., 2021).

    The turnover rates of protein inclusions probably depend on the structures of the constituent filaments, their modifications and association with other molecules. In Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE), extracellular tangles, so-called “tombstones,” predominate at end-stage. This is not true of Pick’s disease (PiD) or corticobasal degeneration (CBD). Over the past four years, we used electron cryo-microscopy to show that tau filament folds differ between AD, CTE, PiD and CBD, with those of AD and CTE being most similar (Fitzpatrick et al., 2017; Falcon et al., 2018; Falcon et al., 2019;  Zhang et al., 2020). Despite these structural differences, tau filaments from brain comprise at least microtubule-binding repeats 3 (R3) and R4, as well as 10-12 amino acids after R4. Constructs K18 and K19 of recombinant tau end at E372, four amino acids after R4 (Gustke et al., 1994). Even though the structures of K18 and K19 filaments are not known, they probably differ from those of tau filaments from human brain.

    The structures of tau filaments from cases with mutations in MAPT are also unknown. As in CBD, 4R tau assembles in some nerve cells and glial cells in individuals with the P301L mutation, with only a small number of extracellular inclusions (Spillantini et al., 1998). Less is known about the effects of mutation S320F (Rosso et al., 2002). There are no known cases of frontotemporal dementia that are caused by both missense mutations. Even so, it may be interesting to know more about the structures and modifications of 0N4R P301L/S320F human tau filaments.

    References:

    . rAAV-based brain slice culture models of Alzheimer's and Parkinson's disease inclusion pathologies. J Exp Med. 2019 Mar 4;216(3):539-555. Epub 2019 Feb 15 PubMed.

    . Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature. 2018 Sep;561(7721):137-140. Epub 2018 Aug 29 PubMed.

    . Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature. 2019 Apr;568(7752):420-423. Epub 2019 Mar 20 PubMed.

    . Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017 Jul 13;547(7662):185-190. Epub 2017 Jul 5 PubMed.

    . Domains of tau protein and interactions with microtubules. Biochemistry. 1994 Aug 16;33(32):9511-22. PubMed.

    . A novel tau mutation, S320F, causes a tauopathy with inclusions similar to those in Pick's disease. Ann Neurol. 2002 Mar;51(3):373-6. PubMed.

    . Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. Am J Pathol. 1998 Nov;153(5):1359-63. PubMed.

    . Novel tau filament fold in corticobasal degeneration. Nature. 2020 Apr;580(7802):283-287. Epub 2020 Feb 12 PubMed.

    View all comments by Michel Goedert
  3. This is a really interesting paper and provides a potentially very useful new tool for studying tau inclusions. Whilst tau tangles have long been reported as a key feature in Alzheimer's disease and other tauopathies, we know surprisingly little about them! As the authors discuss in the paper, we know that tangles can exist for long periods of time within neurons, but the impact on those neurons is somewhat unclear, despite tau tangles being a reasonable correlate of cognitive symptoms in disease. There have been previous reports (e.g. Dejanovic et al., 2018) that show that high levels of phosphorylated tau can result in synapses being labelled by the complement system—targeting them for destruction by microglia—potentially explaining the reduction in synapse density in tauopathies. Other papers, however (Kuchibhotla et al., 2014; Rocher et al., 2010; Rudinskiy et al., 2014), find that tangle-bearing neurons are relatively functional, and can even integrate into functional neuronal circuits. This could indicate that other tau forms, such as soluble oligomers, could be more toxic to the cell.

    The authors use brain-slice cultures, which are an effective ex vivo tool that permits ease of manipulation (such as transfection with viruses and live imaging), in a complex environment that, at least partially, retains neuronal circuits, synaptic connections, and supporting cell types (such as microglia, astrocytes, etc.). It is worth noting that whilst the tissue used is postnatal, this group (Croft et al., 2017, and others, myself included, e.g., Harwell and Coleman, 2016; Durrant et al., 2020) find that AD-like pathological phenotypes partially replicate and occur on an accelerated timescale in slice cultures relative to in vivo.

    This paper addresses a key question about the nature of tau tangles—reporting that these structures are far more dynamic than originally thought. The methodology is neat, using a photo-convertible tau Dendra2 virus to follow turnover of tau as well as inclusion of new protein in the same tangles over time. Their finding that tau tangles are dynamic structures could highlight the potential for increasing tau clearance from the brain and reducing tangle burden if the mechanisms behind turnover can be uncovered.

    One point worth considering, however, is whether, given the assertion in this and other studies that tau tangles themselves may not be overtly harmful to the neurons, clearance of tangles could result in unwanted side effects, such as release of toxic oligomers that are known to have synapse-disrupting properties. This model could provide a useful mechanism for testing this principle, by correlating increased or decreased turnover with measures of neuronal health/synaptic function. The platform would also be a relatively quick and effective drug screening tool for compounds looking to disrupt tau aggregation, or promote tau clearance.

    Interestingly, only mutant tau is found to form aggregates in the culture period, likely reinforcing the dogma that hyperphosphorylated tau is the main component of such tangle structures. Whilst the mutant tau is a very useful experimental tool for this system, it is worth noting that most individuals with tau tangles do not possess tau mutations—so whilst mechanisms are very likely to be similar, extrapolation to the behavior of tangles composed of "wild-type" tau may require additional experimentation.

    The authors maintained the cultures for an impressive length of time (up to 100 days in some cases) and found that the half-life of tau inclusions increased with the increasing age of the slice culture. It would be very interesting to uncover whether this is a sign of reduced slice health due to culture conditions, or a genuine marker of neuronal age showing reduced capacity for tau turnover. If the latter, this could provide a very interesting direction to explore whether age alters responses to tau pathology, or even predisposes to formation of tangles in the first place due to reduced clearance of the aggregates. This could open up understanding of why humans are more susceptible to tauopathies with increasing age.

    Overall, I think the authors present an excellent new tool for exploring tau-tangle turnover mechanisms in neurons and have provided novel insight into the dynamic nature of tau inclusions.

    References:

    . Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies. Neuron. 2018 Dec 19;100(6):1322-1336.e7. Epub 2018 Nov 1 PubMed.

    . Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo. Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):510-4. Epub 2013 Dec 24 PubMed.

    . Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs. Exp Neurol. 2010 Jun;223(2):385-93. PubMed.

    . Tau pathology does not affect experience-driven single-neuron and network-wide Arc/Arg3.1 responses. Acta Neuropathol Commun. 2014 Jun 10;2:63. PubMed.

    . Membrane association and release of wild-type and pathological tau from organotypic brain slice cultures. Cell Death Dis. 2017 Mar 16;8(3):e2671. PubMed.

    . Synaptophysin depletion and intraneuronal Aβ in organotypic hippocampal slice cultures from huAPP transgenic mice. Mol Neurodegener. 2016 Jun 10;11(1):44. PubMed.

    . Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling. Cell Death Dis. 2020 Feb 6;11(2):98. PubMed.

    View all comments by Claire Durrant

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  1. Not Merely Tau Tombstones, Neurofibrillary Tangles Are Dynamic