Nature: New target for Alzheimer's disease, Nanjing University Li Liang/Zeng Ke's team reveals the mechanism of synaptic pruning inhibitory signal abnormality in Alzheimer's disease

Alzheimer's disease (AD), commonly known as "Alzheimer's disease", is a serious neurodegenerative disease.
Patients usually suffer from memory decline and weakened learning ability, accompanied by emotional regulation.
Obstacles and loss of athletic ability greatly affect the development of individuals, families and even society.

Currently, about 50 million people worldwide suffer from Alzheimer's disease.

As the average life expectancy of human beings increases and the aging society intensifies, the prevalence of Alzheimer's disease is also rising.
It is estimated that by 2050, Alzheimer's patients will increase to more than 150 million.

Microglia play a key role in the pruning/clearing of neuronal synapses.
Abnormalities in this process can cause social behavior disorders such as autism in mice as adults.

Signals that regulate synapse pruning are abnormally activated in some neurological diseases, leading to excessive phagocytosis of nerve synapses by microglia and the appearance of corresponding psychiatric symptoms.

On April 1, 2021, Liang Li/Zeng Ke's research group from the School of Life Sciences, Nanjing University published a research paper titled Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration in the journal Nature Communications.

This research system clarified the negative regulatory role of SIRPα signaling in microglia during early synaptic pruning, and 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 research team 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.

On the other hand, studies have found that the expression of SIRPα is significantly decreased in the brain tissues of Alzheimer's disease mouse models and patients.

In the SIRPα-deficient Alzheimer's mouse model, the pathology of amyloid is not changed, but the loss of synapses and cognitive decline increase significantly before the formation of amyloid deposits.

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

The research results reveal the important role of SIRPα signaling in microglia in physiological and pathological processes, and provide a potential target for the treatment of Alzheimer's disease.

Associate Professor Li Liang from the School of Life Sciences 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 from Nanjing University, and Dr.
Zhangpeng Chen from Nanjing University are the joint firsts Author.

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