Why do synapses vanish in the Alzheimer’s brain? In the March 31 Science, researchers make the case that the brain’s resident immune cells, microglia, are to blame. Scientists led by Beth Stevens at Boston Children’s Hospital injected Aβ into wild-type mouse brain, and found that postsynapses rapidly became marked with complement proteins of the innate immune system. Microglia then devoured these structures. Inhibiting the complement cascade pathway at any of several points preserved synapses, even in the presence of Aβ. Stevens previously presented these data at the 2015 Society for Neuroscience meeting in Chicago (see Nov 2015 conference news).
When first author Soyon Hong injected synthetic oligomers of Aβ into wild-type mice, complement C1q and C3 flocked to postsynapses. For the Aβ preparation, Dominic Walsh at Brigham and Women’s Hospital, Boston, cross-linked synthetic S26C Aβ40 to produce dimers, and the authors centrifuged the preparation to remove any large prefibrillar species (see Nov 2010 news). Synapse loss followed injection within 72 hours. Microglia seemed to be the culprits, as fluorescently-labeled synapses accumulated inside these immune cells (see image at left). Blocking the complement pathway, either by treating mice with anti-C1q antibodies or genetically ablating C1q, prevented synaptic loss. Synapses were also preserved after Aβ injection in mice that lacked the CR3 microglial complement receptor, again suggesting that these immune cells were involved in pruning.
Song used additional AD models to confirm the relationship between Aβ and synaptic complement. In J20 mice, which express human mutant APP, C1q and C3 clustered at postsynapses in the hippocampi and frontal cortices when the animals were as young as one month of age. Injecting these mice with a γ-secretase inhibitor to block Aβ production lowered synaptic C1q. In a second AD mouse model, APPPS1, C1q and C3 also accumulated at hippocampal postsynapses.
Stevens and colleagues had previously reported that microglia prune excess synapses in the developing brain (see Dec 2007 news; Mar 2015 conference news). The new data “suggest a local activation of a developmental pruning pathway as a key mechanism underlying oligomeric Aβ-induced synapse loss in pre-plaque AD brain,” they wrote. It is still unclear how Aβ drives complement proteins to synapses. Aβ may directly bind and anchor complement proteins at synapses, or Aβ treatment may expose a synaptic C1q receptor, the authors suggest.—Madolyn Bowman Rogers
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Research Models Citations
- Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 6;352(6286):712-6. Epub 2016 Mar 31 PubMed.