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Alzheimer's disease (AD) is a neurodegenerative disease with insidious onset and progressive development.
It is characterized by β-amyloid protein deposition and abnormal phosphorylation of Tau protein.
For β-amyloid deposits, the currently developed β-amyloid-binding human monoclonal antibody aducanumab can selectively bind to amyloid deposits in the brains of AD patients and activate the immune system.
Remove deposited protein from the brain.
However, the failure of Aducanumab's clinical trial has further led scientists to question the hypothesis of AD's β-amyloid disease.
Meningeal lymphatic vessels can transport waste from brain tissue fluid and cerebrospinal fluid to deep cervical lymph nodes for disposal.
Meningeal lymphatic drainage plays an important role in the accumulation of beta amyloid.
On April 28, 2021, Jonathan Kipnis, professor of neuroscience at the University of Virginia School of Medicine and director of the Brain Immunology and Glial Center, published an article in the journal Nature revealing that impaired meningeal lymphatic drainage exacerbates the microglia inflammatory response in AD.
Researchers found that meningeal lymphatic dysfunction is age-related: there is no meningeal lymphatic dysfunction in 3-month-old and 5-month-old AD model mice, but the upper sagittal sinus is covered in 12-month-old AD model mice Cerebral lymphatic vessels in, transverse sinuses, paranasal sinuses, etc.
decreased, and the number of B cells, CD4 positive T cells and CD8 positive T cells increased significantly.
At the same time, the accumulation of β-amyloid protein increased significantly during this time period.
Researchers injected the verteporfin liposome Visudyne into the cerebrospinal fluid, causing brain lymphatic vessel damage, which can cause anxiety-like symptoms in AD mice and aggravate cognitive dysfunction.
Then they treated adult (2-month-old) AD model mice with normal brain lymphatic vessels and damaged cerebral lymphatic vessels with monoclonal antibodies aducanumab and mAb158, and found that AD mice with normal brain lymphatic vessels received monoclonal antibody treatment.
The accumulation of beta amyloid is reduced.
On the contrary, the accumulation of β-amyloid protein in AD mice with brain lymphatic damage increased after treatment, the number of activated microglia also increased, and the expression of fibrinogen also increased.
These results indicate that the decrease in mouse meningeal lymphatic drainage aggravates the adverse effects of brain fibrinogen levels and neuroinflammation.
They found that compared with mice with cerebral lymphatic vessels, the amount of β-amyloid in the brain parenchyma of mAb158 was significantly reduced after clearing the meningeal lymphatic vessels.
This indicates that the amount of mAb158 transported from the cerebrospinal fluid to the brain parenchyma after meningeal lymphatic disorder is reduced, reducing its therapeutic effect.
Transcriptomics analysis of the endothelial cells, microglia and cerebral vascular endothelial cells of mouse meningeal lymphatic vessels revealed that meningeal lymphatic function is related to the activation of microglia and cerebral blood vessels, and the endothelial cells and vascular endothelium of meningeal lymphatic vessels The cells highly express AD-related genes.
In addition, the gene characteristics of microglia in AD model mice with impaired meningeal lymphatic function overlap with the gene expression profile of activated microglia in the brain of AD patients.
Previous studies have found that promoting the expression of vascular endothelial growth factor C (VEGF-C) in elderly mice can enhance meningeal lymphatic drainage of macromolecular substances into the cerebrospinal fluid and improve learning and memory capabilities.
Researchers injected VEGF-C-expressing virus and mAducanumab into elderly (22-month-old) AD model mice to significantly reduce the deposition of β-amyloid plaques, but injection of mAducanumab alone did not have this effect.
This article reveals that cerebral lymphatic dysfunction aggravates the deposition of fibrinogen and neuro-inflammatory response, which hinders the transport of drugs to the brain parenchyma through the cerebrospinal fluid.
[References] 1.
https://doi.
org/10.
1038/s41586-021-03489-0 The pictures in the article are all from the references
Alzheimer's disease (AD) is a neurodegenerative disease with insidious onset and progressive development.
It is characterized by β-amyloid protein deposition and abnormal phosphorylation of Tau protein.
For β-amyloid deposits, the currently developed β-amyloid-binding human monoclonal antibody aducanumab can selectively bind to amyloid deposits in the brains of AD patients and activate the immune system.
Remove deposited protein from the brain.
However, the failure of Aducanumab's clinical trial has further led scientists to question the hypothesis of AD's β-amyloid disease.
Meningeal lymphatic vessels can transport waste from brain tissue fluid and cerebrospinal fluid to deep cervical lymph nodes for disposal.
Meningeal lymphatic drainage plays an important role in the accumulation of beta amyloid.
On April 28, 2021, Jonathan Kipnis, professor of neuroscience at the University of Virginia School of Medicine and director of the Brain Immunology and Glial Center, published an article in the journal Nature revealing that impaired meningeal lymphatic drainage exacerbates the microglia inflammatory response in AD.
Researchers found that meningeal lymphatic dysfunction is age-related: there is no meningeal lymphatic dysfunction in 3-month-old and 5-month-old AD model mice, but the upper sagittal sinus is covered in 12-month-old AD model mice Cerebral lymphatic vessels in, transverse sinuses, paranasal sinuses, etc.
decreased, and the number of B cells, CD4 positive T cells and CD8 positive T cells increased significantly.
At the same time, the accumulation of β-amyloid protein increased significantly during this time period.
Researchers injected the verteporfin liposome Visudyne into the cerebrospinal fluid, causing brain lymphatic vessel damage, which can cause anxiety-like symptoms in AD mice and aggravate cognitive dysfunction.
Then they treated adult (2-month-old) AD model mice with normal brain lymphatic vessels and damaged cerebral lymphatic vessels with monoclonal antibodies aducanumab and mAb158, and found that AD mice with normal brain lymphatic vessels received monoclonal antibody treatment.
The accumulation of beta amyloid is reduced.
On the contrary, the accumulation of β-amyloid protein in AD mice with brain lymphatic damage increased after treatment, the number of activated microglia also increased, and the expression of fibrinogen also increased.
These results indicate that the decrease in mouse meningeal lymphatic drainage aggravates the adverse effects of brain fibrinogen levels and neuroinflammation.
They found that compared with mice with cerebral lymphatic vessels, the amount of β-amyloid in the brain parenchyma of mAb158 was significantly reduced after clearing the meningeal lymphatic vessels.
This indicates that the amount of mAb158 transported from the cerebrospinal fluid to the brain parenchyma after meningeal lymphatic disorder is reduced, reducing its therapeutic effect.
Transcriptomics analysis of the endothelial cells, microglia and cerebral vascular endothelial cells of mouse meningeal lymphatic vessels revealed that meningeal lymphatic function is related to the activation of microglia and cerebral blood vessels, and the endothelial cells and vascular endothelium of meningeal lymphatic vessels The cells highly express AD-related genes.
In addition, the gene characteristics of microglia in AD model mice with impaired meningeal lymphatic function overlap with the gene expression profile of activated microglia in the brain of AD patients.
Previous studies have found that promoting the expression of vascular endothelial growth factor C (VEGF-C) in elderly mice can enhance meningeal lymphatic drainage of macromolecular substances into the cerebrospinal fluid and improve learning and memory capabilities.
Researchers injected VEGF-C-expressing virus and mAducanumab into elderly (22-month-old) AD model mice to significantly reduce the deposition of β-amyloid plaques, but injection of mAducanumab alone did not have this effect.
This article reveals that cerebral lymphatic dysfunction aggravates the deposition of fibrinogen and neuro-inflammatory response, which hinders the transport of drugs to the brain parenchyma through the cerebrospinal fluid.
[References] 1.
https://doi.
org/10.
1038/s41586-021-03489-0 The pictures in the article are all from the references
