14 Oct 2023

Neurofibrillary tangles, the hallmark of tauopathies, are closely linked to failing cognition. So are tau oligomers, suggest scientists led by Teresa Gómez-Isla at Massachusetts General Hospital in Boston. In the October 9 JAMA Neurology, they reported that, in people with Alzheimer’s disease, synapses were packed with the oligomers and there were fewer of them than in healthy controls. Remarkably, in others who had similar plaque and tangle load yet were cognitively normal, synapses containing tau oligomers were sparse. Microglia and astrocytes in tissue from dementia cases carried more oligomer-positive synaptic fragments, hinting that these cells had trimmed the neural connections. “Synaptic loss in AD may be primarily associated with aberrant engulfment of synaptic elements by microglia and astrocytes rather than with Aβ plaques or neurofibrillary tangles,” the authors concluded. Others had come to similar conclusions from studying mice, but this was only recently described in AD.

“This study presents an elegantly executed exploration of [the] selective vulnerability [of neurons], incorporating rigorous pathoanatomical insights,” Lea Tenenholz Grinberg, University of California, San Francisco, wrote in an accompanying editorial. Amy Pooler of Sangamo Therapeutics, San Francisco, also praised the work, calling it incredibly thorough. “[It] enabled, for the first time, a very detailed look into the interactions between synapses, astrocytes, and microglia as they relate to cognitive decline,” she wrote (comment below).

Researchers have captured microglia and astrocytes devouring synapses and even feeble neurons in mice (Jun 2020 news; Jul 2018 conference news; Aug 2013 conference news). Last month, scientists led by Tara Spires-Jones at the University of Edinburgh, U.K., reported the first direct evidence that this happens in AD, too. They spotted microglia and astrocytes laden with synaptic material in cortical tissue taken postmortem (Sep 2023 news). “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,” wrote Spires-Jones and Makis Tzioras in her lab (comment below).

What lures the glia to prune synapses? To better understand this, first author Raquel Taddei analyzed visual cortex tissue from 40 people who had donated their brains to the Massachusetts Alzheimer Disease Research Center Brain Bank. Studying the visual cortex allowed the scientists to determine if synapse loss precedes tau tangles because this area of the brain remains tangle-free until very late in the disease. Among the participants, 32 had moderate tau pathology, clocking in at Braak stages III or IV. Nineteen of these had had early stage dementia. The other 13 had been cognitively healthy and the authors designated them as being resilient.

To see what might preserve neural connections, Taddei isolated synaptosomes from the brain tissue and measured various phosphorylated forms and oligomers of tau. Only the latter differed between the AD and resilient samples, with the former containing twice as much as the latter.

To get a clearer picture of what happens at synapses, Taddei used expansion microscopy, a technique where a polymer gel is injected into neurons and nearby glia to swell them to 4.5 times their normal size before taking three-dimensional images using a confocal microscope (Chen et al., 2015; reviewed by Gallagher and Zhao, 2021). This technique can resolve fine cellular processes, including individual synapses. With these high-resolution images, Taddei found that microglia and astrocytes in AD tissue contained about twice as many oligomer-positive synapses as did glia in tissue from controls or resilient cases (image below). In fact, in AD tissue samples, almost all the synaptic puncta within microglia and two-thirds of the puncta in astrocytes had tau oligomers, meaning that the glia preferred to prune synapses with the soluble tau.

Glia in Action. Three-dimensional renderings of a human microglia (left) and an astrocyte (right) that had engulfed post-synapses (teal) or pre-synapses (green) containing tau oligomers (red). White arrowheads indicate examples of engulfed synapses; yellow arrowheads show two free synapses. [Courtesy of Taddei et al., JAMA Neurology, 2023.]

This preferential pruning likely explains the synapse loss seen in AD, even at early disease stages, the authors believe. Indeed, microglia and astrocytes in AD tissue engulfed fivefold more synaptic material than did cells in cognitively resilient or control tissue. The resilient donors had as many synapses as did controls, while people with AD had 38 percent fewer. “The correlation between cognitive decline and the reduction in the number of mature synapses is striking,” Pooler noted.

Only in Dementia. Compared to controls (C) and cognitively resilient people (R), people with dementia (D) had one-third fewer synapses (left) and five times as many synapse-stuffed microglia (middle) and astrocytes (right). [Courtesy of Taddei et al., JAMA Neurology, 2023.]

Scientists led by Cristian Lasagna-Reeves of Indiana University School of Medicine, Indianapolis, found a similar dichotomy when studying tau seeding near plaques. Despite both resilient and AD tissue being awash in neurofibrillary tangles, they found much more soluble oligomeric tau in the latter (Jury-Garfe et al., 2023). “The oligomerization of tau at synapses might be an aggregation pathway, independent of tangle formation, that spurs microglial pruning,” Lasagna-Reeves told Alzforum.—Chelsea Weidman Burke

Comments

1. • Amy Pooler
     Sangamo Therapeutics
   • Posted: 14 Oct 2023

   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. • Tara Spires-Jones
     University of Edinburgh
   • Makis Tzioras
     The University of Edinburgh
   • Posted: 14 Oct 2023

   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 Tara Spires-Jones View all comments by Makis Tzioras

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References

News Citations

1. Too Phatal: How Microglia, Astrocytes Snuff Out Dying Neurons 26 Jun 2020
2. Synaptic Tau Clangs the Dinner Bell for Hungry Microglia 17 Jul 2018
3. Curbing Innate Immunity Boosts Synapses, Cognition 8 Aug 2013
4. In Alzheimer Brain, Can Synaptic Pruning Be Good? 8 Sep 2023

Paper Citations

1. Chen F, Tillberg PW, Boyden ES. Optical imaging. Expansion microscopy. Science. 2015 Jan 30;347(6221):543-8. Epub 2015 Jan 15 PubMed.
2. Gallagher BR, Zhao Y. Expansion microscopy: A powerful nanoscale imaging tool for neuroscientists. Neurobiol Dis. 2021 Jul;154:105362. Epub 2021 Apr 2 PubMed.
3. Jury-Garfe N, You Y, Martínez P, Redding-Ochoa J, Karahan H, Johnson TS, Zhang J, Kim J, Troncoso JC, Lasagna-Reeves CA. Enhanced microglial dynamics and paucity of tau seeding in the amyloid plaque microenvironment contributes to cognitive resilience in Alzheimer's disease. bioRxiv. 2023 Jul 28; PubMed.

Further Reading

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