​Nat Commun | Li Liang/Zeng Ke's team reveals the mechanism of the abnormal synaptic pruning inhibitory signal in Alzheimer's disease

Responsible editor | Enzyme microglia play a key role in the pruning/clearing of neuronal synapses.

During the early development of the nervous system, the synaptic region promotes the pruning of redundant synapses by microglia through positive regulation signals (iC3b/C3b-CR3).

Obstacles in this process will lead to abnormal behaviors of mice after adulthood, resulting in social behavior disorders such as autism [1, 2].

The above-mentioned signal pathways are abnormally activated in some neurological diseases, leading to the excessive phagocytosis of nerve synapses by microglia and the appearance of corresponding psychiatric symptoms [3].

How can microglia eliminate redundant structures while retaining normal synapses? This requires the synergy of two-way regulatory signals (promoting/inhibiting pruning).

In 2018, it was reported for the first time that the CD47 molecules of neurons are involved in the negative regulation of synaptic pruning during the early development of the nervous system.
It is speculated that CD47 of neurons and SIRPα of microglia combine to produce a "do not eat me" signal to help microglia recognize The synaptic structure that needs to be preserved [4].

However, it is not clear whether the SIRPα signal of microglia regulates synaptic pruning/clearance under physiological and pathological conditions.

Recently, Liang Li/Zeng Ke’s group from the School of Life Sciences, Nanjing University published an article Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration in Nature Communications, which systematically clarified the role of SIRPα signaling in microglial cells in synaptic pruning during early development.
Negative regulation, and it was reported for the first time that the abnormal signal is involved in the synaptic pathology of Alzheimer's disease.Using microglia-specific SIRPα knockout mice, the researchers found that SIRPα loss caused a decrease in synaptic density in the early developmental stage and increased synaptic phagocytosis of neurons by microglia.

Blocking SIRPα in microglia or CD47 in neurons can increase the phagocytosis of synapses by microglia.

In addition, inhibiting the electrical activity of neurons in animal models can reduce the expression of CD47 at synapses, allowing microglia to preferentially eliminate these synapses.

The above results suggest that microglia SIRPα and neuron CD47 interact to produce signals that protect synapses from microglia phagocytosis.

The previous research of the research group found that the expression of SIRPα in microglia decreased during the aging process [5].

On the other hand, inhibiting neural activity can reduce the expression of synaptic CD47.
Researchers thought of Alzheimer's Disease (AD), which has both characteristics of aging and decreased neural activity.

Studies have found that the expression of SIRPα is significantly decreased in AD mouse models and in the brain tissues of patients.
In AD mouse models with SIRPα deficiency, amyloid pathology remains unchanged, but synapse loss and cognitive decline are formed in amyloid deposits.
Significant increase before.

Through the study of genetic model and drug model, it is finally proved that the down-regulation of SIRPα signal of microglia in AD disease promotes its excessive phagocytosis of nerve synapses.

In addition, the researchers also found that the expression of CD47 in neuronal synaptosomes in AD model mice is down-regulated and is more likely to be phagocytosed by microglia.

The research results reveal the important role of the SIRPα signal of microglia in the physiological and pathological processes, and provide a potential target for the treatment of AD diseases.

When talking about the significance of the discovery of this signal in neurological diseases, Li Liang said: "Our current work proves that the SIRPα signal of microglia plays a negative role in the process of synaptic pruning, and this abnormal signal is also involved.
Synaptic pathology of
AD.
The change of CD47 signal in AD is also an interesting question, because its expression is directly related to the electrical activity of neurons. Many neurological diseases have synaptic pathology, and whether there is any change in SIRPα-CD47 signal is also what we want to know.

"Associate Professor Li Liang of Nanjing University, Professor Zeng Ke is the co-corresponding author of the paper, Ding Xin, a PhD student at Nanjing University, Dr.
Jin Wang from the Department of Endocrinology, Gulou Hospital, Master Student Huang Miaoxin of Nanjing University, and Dr.
Zhangpeng Chen from Nanjing University are the co-first authors of the paper. Original link: Platemaker: 11 References 1.
Zhan, Y.
et al.
Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior.
Nat Neurosci 17, 400-406 (2014).
2.
Paolicelli, RC et al.
Synaptic pruning by microglia is necessary for normal brain development.
Science 333, 1456-1458 (2011).
3.
Sellgren, CM et al.
Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.
Nat Neurosci 22, 374-385 (2019).
4.
Lehrman, EK et al.
CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development.
Neuron 100, 120-134 e126 (2018).
5.
Wang, J.
et al.
SIRPalpha deficiency accelerates the pathologic process in models of Parkinson disease.
Glia 67(12):2343-2359 (2019).
Notes for reprinting 【Non-original article 】The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated.