Taddei RN, Perbet R, Mate de Gerando A, Wiedmer AE, Sanchez-Mico M, Connors Stewart T, Gaona A, Melloni A, Amaral AC, Duff K, Frosch MP, Gómez-Isla T. Tau Oligomer-Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease. JAMA Neurol. 2023 Nov 1;80(11):1209-1221. PubMed.

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  1. The authors performed incredibly thorough analyses of synaptic structure in postmortem human brain which enabled, for the first time, a very detailed look into the interactions among synapses, astrocytes, and microglia as they relate to cognitive decline. The correlation between the presence of cognitive decline and the reduction in number of mature synapses is striking. What is particularly exciting about this work, though, is the possibility of a newly uncovered mechanism of oligomeric tau toxicity—its accumulation in synapses may lead to preferential synaptic engulfment by either microglia or astrocytes.

    However, this observation raises a new set of interesting questions: Is the oligomeric tau "marking" the synapses for removal, rendering them nonfunctional, or something else? How do "resilient" brains, which harbor a similar pathology burden, escape the synaptic accumulation of oligomeric tau, and therefore the loss of mature synapses? Is it related to a more general reduction of glial inflammatory response which may reduce the propensity of those cells to engage in tau-related synaptic elimination? Very much looking forward to follow-up work on this topic!

    View all comments by Amy Pooler

  2. It is fantastic to see confirmation of our study, published earlier this year, that human microglia and astrocytes engulf synapses in Alzheimer’s disease (Tzioras et al., 2023). Both of our studies found more synapses inside astrocytes than inside microglia, which I think is a very important finding for directing future therapeutic approaches. It was also very cool to see tau-oligomer-containing synapses within glia in this study because we have recently seen that oligomeric tau likely spreads trans-synaptically in human brain (Colom-Cadena et al., 2023). 

    A novel aspect of this study is the important finding that glial engulfment of synapses is associated with cognitive impairment. An important question for all of us moving forward is whether the synapses that are being engulfed are dysfunctional (as implied by the finding here that they often contain tau oligomers) or whether this engulfment is damaging functional synapses, thus directly contributing to cognitive decline.

    References:

    Tzioras M, Daniels MJ, Davies C, Baxter P, King D, McKay S, Varga B, Popovic K, Hernandez M, Stevenson AJ, Barrington J, Drinkwater E, Borella J, Holloway RK, Tulloch J, Moss J, Latta C, Kandasamy J, Sokol D, Smith C, Miron VE, Káradóttir RT, Hardingham GE, Henstridge CM, Brennan PM, McColl BW, Spires-Jones TL. Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8. Cell Rep Med. 2023 Sep 19;4(9):101175. Epub 2023 Aug 30 PubMed.

    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.

    View all comments by Makis Tzioras

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  1. In Alzheimer’s, Tau Oligomers in Synapses Act as ‘Eat Me’ Signal