Complement each other's strengths and complement each other's weaknesses, win-win cooperation! Scientists have revealed astrocytes and microglia "complementary" phagocytic synapses

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Microglial and astrocyte-mediated synaptic pruning is critical
to shaping the correct neural connections during brain development.
In the pathological state, excessive pruning of these glial cells causes abnormal loss of
synapses.
Overactivation of classical complement pathways in Alzheimer's disease (AD) patients and mouse model brains leads to neuronal damage and synaptic loss
.
Patients with AD have abnormally elevated
complement molecules in the brain and cerebrospinal fluid.
On September 20, 2022, the research team of Jesse E.
Hanson of the world-renowned Gene Tektronix Biotechnology Company revealed that astrocytes selectively phagocytic excitatory synapses in AD mouse models, microglia selectively phagocytic inhibitory synapses, and this selectivity relies in part on the complement system
.

Figure 1: AD model mouse brain volume atrophy

Magnetic resonance imaging technology found that the total brain volume of P301S model mice aged 6 months to 9 months was significantly reduced, the volume of the hippocampus region was also reduced, and there was excessive activity, and knocking out c1q could significantly attenuate this reduction in brain volume and inhibit overactivity
.

Proteomics technology found that 6-month-old P301S model mice hippocampal brain region 108 kinds of synaptic protein expression down-regulation, 68 kinds of synaptic protein expression up-regulation, accounting for about 2.
5% of the total synaptic protein, while 9-month-old 301S model mice hippocampal brain region expression of 253 kinds of synaptic protein expression down-regulation, 434 kinds of synaptic protein expression up-regulation, accounting for about 16.
5%
of the total synaptic protein.
The synaptic protein changes in the hippocampus brain region of both 301S model mice at 6 months of age and 9 months of age after knockout of C1q were significantly reduced
.

The 55 proteins in the P301S model mouse hippocampal brain region with the most upregulated synaptic protein expression are mainly secreted
by astrocytes.
Specifically, the protein most added in the hippocampal synaptic fraction of P301S mice is astrocyte-specific mitochondrial proteins
.
The most downregulated proteins are secreted
mainly by excitatory neurons.
These abnormally upregulated astrocyte-derived synaptic proteins are expressed normally
after knocking out C1q.

Figure 2: AD model glial cell selective phagocytic synapses

The number of phagocytic excitatory synapses and inhibitory synapses in the hippocampal brain region of the P301S model increased, the number of astrocyte phagocytes phagocytic these two synapses also increased, and the number of microglia and astrocytes phagocytic excitatory synapses and inhibitory synapses decreased
after knockout C1q.

But knocking out c1q in healthy adult mice does not affect the number of
glial cell phagocytic synapses.
Surprisingly, the P301S model mouse hippocampal brain region astrocytes have more phagocytic excitatory synapses and microglia more phagocytic inhibitory synapses
.

Studies have shown that microglia-specific TREM2 gene deletion mutations increase the risk of AD, while TREM2 deletions in AD mouse models impair the ability and phagocytic activity
of microglia to migrate to aβ plaques.
Astrocytes and microglia engorge more excitatory and inhibitory synapses
around plaques in AD model mice than in plaque-free regions.

After knocking out TREM2, the number of small glial phagocyte phagocyte excitatory synapses in mice in AD model mice was significantly reduced, but it did not affect the function of
astrocytes phagocytic excitatory synapses.
However, knockout of TREM2 promotes phagocytic inhibitory synapses
in mouse astrocytes in AD models.
This suggests that astrocytes in a disease state compensate for microglial phagocytic dysfunction
.

summary

In this paper, it was found that knockout of complement c1q inhibited glial phagocytic synapses, and astrocytes could exercise microglial phagocyte phagocytic function after microglial phagocytic dysfunction
.

【References】

1.
Dejanovic, B.
, Wu, T.
, Tsai, MC.
 et al.
 Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models.
 Nat Aging 2, 837–850 (2022).
 

https://doi.
org/10.
1038/s43587-022-00281-1

The images in the article are from references