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Microglia are triggered to engulf, or eat, synapses 鈥� the connections between neurons 鈥� in the early stages of Alzheimer鈥檚 disease. This process, known as phagocytosis, leads to the loss of synapses, and this correlates strongly with cognitive decline. However, it is not yet known whether specific synapses are targeted, what the triggers are, or why the process occurs.

In the new study,听published in the journal EMBO, the team first showed that microglia preferentially eat synapses from Alzheimer鈥檚 brain samples, over healthy controls. They then set out to determine exactly how microglia know which synapses to eat.

Previous studies have shown that, in the context of the developing brain, synapses externalize a molecule known as phosphatidylserine, which signals to microglia to come and engulf them. The new study from the Hong lab shows that a similar mechanism occurs in the Alzheimer鈥檚 brain. Using rodent neurons, the researchers revealed that when misfolded amyloid protein is applied to synapses, they express on the surface the 鈥榚at-me鈥� molecule phosphatidylserine, which recruits microglia to come and engulf the synapses.

Dr Hong explained: 鈥淚mportantly, our study shows that this is an active process, it is not a case of synapses falling off and microglia cleaning up the debris, as was previously considered. We now know that microglia are actively removing synapses, and the process is mediated by this molecular signal, phosphatidylserine.鈥�

Next, the researchers aimed to investigate whether microglia are acting in a protective or detrimental capacity in the context of early Alzheimer鈥檚. It is known that early in the disease process, there is hyperactivity in synapses. In a further experiment, Dr Hong鈥檚 team showed that the hyperactive synapses release phosphatidylserine. The researchers measured the firing of synapses over time, and showed that when microglia are present, they engulf these hyperactive synapses and firing returns to baseline levels.

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Dr Hong added: 鈥淥ur results suggest that microglia are carrying out a protective mechanism, to help reduce hyperactivity in neurons in early Alzheimer鈥檚 disease and maintain a state of homeostasis in the cells. This study provides useful insight into how microglial function could be targeted in disease."

The study also shows a protective role for TREM2, a protein on microglia, which is needed to recognise the phosphatidylserine signal from synapses. In microglia where TREM2 is no longer functional, microglia were unable to recognise the 鈥榚at-me鈥� signal, leading to sustained neuronal hyperactivity.

The team is now examining more closely the precise mechanisms by which microglia recognise the phosphatidylserine signal and the link between neuronal hyperactivity and microglia-synapse engulfment in an in vivo context. The researchers hope this knowledge could in future be used to understand the link between two fundamental phenotypes between neuronal hyperactivity and microglia-mediated synapse loss and help develop new therapies for Alzheimer鈥檚.

Links

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• Rueda-Carrasco J, Sokolova D, Lee SE, Childs T, Jur膷谩kov谩 N, Crowley G, De Schepper S, Ge JZ, Lachica JI, Toomey CE, Freeman OJ, Hardy J, Barnes SJ, Lashley T, Stevens B, Chang S, Hong S. . EMBO J. 2023 Aug 14:e113246. doi: 10.15252/embj.2022113246

Banner image: Homer1 (green)- and synaptotagmin1/2 (magenta)-immunoreactive synapses express 鈥榚at-me鈥� signal phosphatidylserine as marked by PSVue643 (yellow) in the hippocampus of NL-F KI; Trem2 R47H KI mice. Credit: Javier Rueda-Carrasco,听

Video: Microglia eating synapses that are expressing the eat-me signal ePtdSer Credit: Sang-Eun Lee,听

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