Colom-Cadena M, Davies C, Sirisi S, Lee JE, Simzer EM, Tzioras M, Querol-Vilaseca M, Sánchez-Aced É, Chang YY, Holt K, McGeachan RI, Rose J, Tulloch J, Wilkins L, Smith C, Andrian T, Belbin O, Pujals S, Horrocks MH, Lleó A, Spires-Jones TL. Synaptic oligomeric tau in Alzheimer's disease - A potential culprit in the spread of tau pathology through the brain. Neuron. 2023 Jul 19;111(14):2170-2183.e6. Epub 2023 May 15 PubMed.

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  1. Colom-Cadena’s study presents compelling structural evidence suggesting that accumulation of tau oligomers at presynaptic terminals is an early event in Alzheimer’s disease neuropathology, which may lead to anterograde transsynaptic spreading first, and to the regional distribution of tau neuropathology later in disease.

    In addition to the technological elegance of the experiments and the finding that oligomeric forms of tau are a major component in synapses compared with other phosphorylated or misfolded tau forms, this work also suggests a potential mechanism to explain how tau spreading is an activity-dependent phenomenon, which has important relevance for therapeutical approaches in development, including noninvasive ones. Because the technical advance in this study can be used to target specific synapses, it will be very interesting to see future studies where additional types of synapses, e.g., inhibitory, are studied using the same approach and technology.

    View all comments by Agenor Limon

  2. In this outstanding paper, Colom-Cadena and colleagues present a beautiful set of array tomography and immunoelectron microscopy experiments showing accumulation of oligomeric tau in the synapses of AD patients. Over the last years, several studies have highlighted the critical importance of synaptic tau for the development and progression of pathology in animal models (Hoover et al., 2010; Largo-Barrientos et al., 2021; Tai et al., 2012). Previous work from the groups of Karen Duff and Tara Spires-Jones already showed that pathogenic tau can spread from pre- to postsynapses in the mouse brain (Liu et al., 2012; Pickett et al., 2017). Now, this article provides the first-time evidence of trans-synaptic spread of oligomeric tau in the human brain.

    The authors use three antibodies to label oligomeric (T22), misfolded (Alz50), and phosphorylated (AT8) tau and find all three species in synapses of AD brains, with a higher presence of oligomeric tau. T22-positive tau oligomers are found on presynaptic vesicles as well as near the postsynaptic density. Interestingly, oligomeric tau is sometimes associated with fibrils in neurofibrillary tangles (NFTs), but synaptic tau oligomers are preferentially found in areas with no (or low numbers of) NFTs. Finally, synaptic tau oligomers are more frequently found only at the presynapse, followed by at both the pre- and postsynapse, while being only at the postsynapse was rare. This suggests to the authors that propagation of tau oligomers occurs from pre- to postsynapse.

    Whether soluble or aggregated tau is the major source of toxicity has been debated for years. Tau oligomers are somehow controversial, and represent a heterogenous intermediate state of soluble tau species with seeding capacity. This study suggests that oligomeric tau species are at least relevant for the progression of the pathology at early stages. Further biochemical and structural characterization of the oligomers that the authors find enriched in synapses of AD brains will be essential to strengthen their findings.

    Another open question in the field is how does tau pathology propagate throughout the different brain regions: Do seeds physically move from one region to another (and if so, how?) or do different brain regions become subsequently vulnerable and start accumulating pathogenic tau species? This work provides indirect evidence supporting the first option, with oligomeric tau being transmitted from one neuron to the next in a trans-synaptic (from pre- to postsynapse) pattern. However, the precise mechanisms by which this transmission occurs in the AD brain (released with synaptic vesicles, through lysosomal exocytosis, in exosomes, or transported in extracellular vesicles or via nanotubes, etc.) remain to be fully elucidated.

    References:

    Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Pitstick R, Carlson GA, Lanier LM, Yuan LL, Ashe KH, Liao D. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010 Dec 22;68(6):1067-81. PubMed.

    Largo-Barrientos P, Apóstolo N, Creemers E, Callaerts-Vegh Z, Swerts J, Davies C, McInnes J, Wierda K, De Strooper B, Spires-Jones T, de Wit J, Uytterhoeven V, Verstreken P. Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation. Neuron. 2021 Mar 3;109(5):767-777.e5. Epub 2021 Jan 19 PubMed.

    Tai HC, Serrano-Pozo A, Hashimoto T, Frosch MP, Spires-Jones TL, Hyman BT. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am J Pathol. 2012 Oct;181(4):1426-35. PubMed.

    Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, Duff K. Trans-synaptic spread of tau pathology in vivo. PLoS One. 2012;7(2):e31302. PubMed.

    Pickett EK, Henstridge CM, Allison E, Pitstick R, Pooler A, Wegmann S, Carlson G, Hyman BT, Spires-Jones TL. Spread of tau down neural circuits precedes synapse and neuronal loss in the rTgTauEC mouse model of early Alzheimer's disease. Synapse. 2017 Jun;71(6) Epub 2017 Mar 6 PubMed.

    View all comments by Pablo Largo-Barrientos

  3. This study represents an impressive use of fluorescence light microscopy to image and quantify tau within thousands of synapses in postmortem brain tissue from a large number of individuals with AD. The dysfunction and loss of synapses are early pathological changes in AD and are highly correlated with cognitive decline (Terry et al., 1991). It is hypothesized that assembled tau within synapses may mediate their dysfunction and loss. In addition, assembled tau may traverse synapses to spread within connected brain regions.

    The authors found tau within pre- and postsynaptic compartments in individuals with AD, which was greatly elevated compared to control individuals. The authors detected abnormally phosphorylated synaptic tau using the antibodies AT8 (pS202 and pT205 tau) and AT180 (pT231 tau), as well as tau immunoreactive against the antibody Alz50. The latter antibody was raised against brain homogenates from individuals with AD and recognizes a discontinuous epitope present on tau filaments (Jicha et al., 1997). 

    The present results extend previous studies of mouse models (Kopeikina et al., 2013) and of synapses fractionated from postmortem brain tissue (Fein et al., 2008). The quantitative approach of Colom-Cadena et al. revealed an asymmetric distribution of synaptic tau favoring the presynaptic compartment. In addition, it was rare for tau to be present in the postsynaptic compartment in the absence of presynaptic tau. These results suggest that tau may preferentially accumulate in the presynaptic compartment and may subsequently induce tau accumulation in the postsynaptic compartment, possibly by direct transfer.

    The authors conclude that oligomeric tau is present in synapses based on labelling with the antibody T22. This antibody, which was raised against recombinant tau seeded with synthetic Aβ42, was reported to detect an oligomeric, non-filamentous form of tau in the soluble brain fraction of individuals with AD (Lasagna-Reeves et al., 2012). However, T22 also exhibited some reactivity against tau filaments in that study (Lasagna-Reeves et al., 2012). In addition, the soluble brain fraction of individuals with AD was recently shown to contain tau filaments (Stern et al., 2023, supplemental figures). Therefore, it is possible T22 recognized tau filaments in the synapses studied by Colom-Cadena et al. Additional studies are required to identify the molecular species of tau present in synapses in the brains of individuals with AD.

    View all comments by Benjamin Ryskeldi-Falcon

  4. It would be interesting to investigate anterograde transsynaptic spreading of tau oligomers, and also which particular species of these tau oligomers are present in the postsynaptic terminal. Another important experiment is to characterize these tau oligomers with MC1, a conformation-dependent antibody (epitope within aa 312-322). Structural characterization of these oligomers in synapses of AD and other tauopathies brains will be essential for exploring therapeutic modalities.

    View all comments by Suhail Rasool

  5. This study by the Spires-Jones group shows accumulation of tau oligomers in pre- and postsynaptic terminals, including in regions with low or no NFT presence. This work provides beautiful and precise quantification of pre- vs. postsynaptic localization, and confirms and extends previous work by us and others supporting synaptic spread of tau pathology using human postmortem samples.

    With respect to extracellular vesicle spread, tau oligomers have also been shown on extracellular vesicles (EVs) released from human AD synapses (Miyoshi et al., 2021). These EVs demonstrated seeding activity in tau biosensor cells.

    It is also possible that p-tau aggregation is directly driven by synaptic oligomeric Aβ prior to anterograde and retrograde spread across synapses. In a 2016 paper (Bilousova et al., 2016), we used parietal cortex samples from early stage disease (Braak II-III) to quantify p-tau and Aβ by flow cytometry on an individual terminal basis. Aβ-positive synaptosomes showed a more than twofold increase in p-tau relative to the total population in multiple regions. Importantly, early stage samples from hippocampus and entorhinal cortex showed a strong correlation between synaptic Aβ and p-tau levels by flow cytometry.

    Taken together with multiple lines of evidence, including the exclusive initial appearance of Aβ in the neocortex before dementia onset, these experiments suggest that a prion-like mechanism of endogenous templated protein corruption may occur in early disease (Walker et al., 2013). 

    References:

    Bilousova T, Miller CA, Poon WW, Vinters HV, Corrada M, Kawas C, Hayden EY, Teplow DB, Glabe C, Albay R 3rd, Cole GM, Teng E, Gylys KH. Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases. Am J Pathol. 2016 Jan;186(1):185-98. PubMed.

    Miyoshi E, Bilousova T, Melnik M, Fakhrutdinov D, Poon WW, Vinters HV, Miller CA, Corrada M, Kawas C, Bohannan R, Caraway C, Elias C, Maina KN, Campagna JJ, John V, Gylys KH. Exosomal tau with seeding activity is released from Alzheimer's disease synapses, and seeding potential is associated with amyloid beta. Lab Invest. 2021 Dec;101(12):1605-1617. Epub 2021 Aug 30 PubMed.

    Walker LC, Diamond MI, Duff KE, Hyman BT. Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol. 2013 Mar 1;70(3):304-10. PubMed.

    View all comments by Karen Gylys

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