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). 

Synaptic Feast.

A hippocampal microglial cell (red) digesting synapses (green) after injection of Aβ. [Courtesy of Science/AAAS.]

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

Comments

  1. This is another thought-provoking study led by Stevens, Selkoe, and Lemere showing an oligomeric Aβ-induced, complement-dependent loss of synapses in early (i.e., pre-plaque) stages of amyloid pathology in transgenic APP models of cerebral amyloidosis. The results nicely fit with our original observations of subtle, pre-plaque CNS inflammation in Alzheimer’s disease-like pathology (Ferretti et al., 2011). In particular, they provide a mechanistic explanation for our finding of intermediate microglia activation associated with incipient cognitive deficits and intraneuronal Aβ-oligomeric material at the pre-plaque stage in APP mouse (Ferretti et al., 2011 and 2012) and rat models (Hanzel et al., 2014).

    Evidence for early, disease-aggravating, pre-plaque pro-inflammatory process is emerging (Ferretti and Cuello, 2011). As a case in point, in the Alzheimer’s Disease Anti-inflammatory Prevention Trial, NSAIDs (naproxen or celecoxib) were effective in improving cognition only at the asymptomatic phase, and not in individuals with overt Alzheimer’s symptoms (Breitner et al., 2011). In addition, earlier studies in Down’s syndrome revealed increased astrogliosis and IL-1 levels at the neonatal stage, decades before the development of advanced Alzheimer’s pathology (Griffin et al., 1989). In a recent investigation, Wilcock and colleagues further demonstrated that the Alzheimer-asymptomatic stage in Down’s syndrome is characterized by exacerbated neuroinflammation (Wilcock et al., 2015). In line with this observation, our work in collaboration with Dr. Caraci (University of Catania, Italy) and Dr. Cuello (McGill University, Canada) indicates elevation of inflammatory markers at the pre-dementia stage in individuals with trisomy 21, correlating with prospective cognitive decline over a two-year period (Iulita et al., 2016, and under revision). 

    The role of inflammation during the progression of the amyloid pathology remains to be elucidated. As the authors point out, complement activation might play completely opposite roles at different stages of the pathology; it is very likely that, while early complement activation leads to detrimental synaptic loss, late plaque-associated activation supports beneficial amyloid phagocytosis. Experiments in older APP-PS1 mice, as well as other transgenic models, would help address this point. Indeed, the characterization of microglial activation in early and late stages of amyloid pathology is crucial to identify suitable therapeutic targets.

    References:

    . Intracellular Aβ-oligomers and early inflammation in a model of Alzheimer's disease. Neurobiol Aging. 2011 Mar 15; PubMed.

    . Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. J Neuroinflammation. 2012;9:62. PubMed.

    . Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2249-62. Epub 2014 Mar 28 PubMed.

    . Does a pro-inflammatory process precede Alzheimer's disease and mild cognitive impairment?. Curr Alzheimer Res. 2011 Mar;8(2):164-74. PubMed.

    . Extended results of the Alzheimer's disease anti-inflammatory prevention trial. Alzheimers Dement. 2011 Jul;7(4):402-11. PubMed.

    . Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7611-5. PubMed.

    . Down syndrome individuals with Alzheimer's disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer's disease. Neurobiol Aging. 2015 Sep;36(9):2468-74. Epub 2015 May 30 PubMed.

    . A Link Between Nerve Growth Factor Metabolic Deregulation and Amyloid-β-Driven Inflammation in Down Syndrome. CNS Neurol Disord Drug Targets. 2016;15(4):434-47. PubMed.

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References

News Citations

  1. Microglia Control Synapse Number in Multiple Disease States
  2. Aβ Neurotoxicity—Is it the Dimer? No, and Yes
  3. Paper Alert: Does the Complement Devour Synapses?
  4. Microglia Rely on Mixed Messages to Select Synapses for Destruction

Research Models Citations

  1. J20 (PDGF-APPSw,Ind)
  2. APPswe/PSEN1dE9

Further Reading

Primary Papers

  1. . Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 6;352(6286):712-6. Epub 2016 Mar 31 PubMed.