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▎WuXi AppTec content team editor
Whether it is amyloid and tau proteins, which are high-risk factors for Alzheimer's disease β or synuclein, the culprit of Parkinson's disease, α synuclein, many neurodegenerative diseases are marked by abnormal aggregation
of damaging proteins.
To help these patients, scientists have been looking for ways to target these protein aggregates, although progress is still limited
.
The Nature paper today shows a potential new direction in which immune cells around the brain can improve the brain's efficiency at removing waste, helping to reduce the aggregation
of toxic proteins.
According to their observations, both the brains of aged mice and Alzheimer's model mice lacked some special immune cells
.
This means that maintaining the function of these special immune cells may be a way
to slow down brain aging and even treat neurodegenerative diseases.
Jonathan Kipnis, a professor of pathology at the University of Washington and corresponding author of the study, said: "Alzheimer's disease research has mostly focused on neuronal death in the past, but in fact many other types of cells also play an impact
on disease development.
”
Professor Kipnis, who has worked in the field of neuroimmunology for many years, discovered back in 2015 that there is a special vascular network in the brain that directs immune cells and some small molecules from the brain to the lymph nodes, and this special system seems to help maintain brain health
.
For example, he found that increasing the efficiency of cerebrospinal fluid and waste products in this system to export to the brain at the same time as conventional Alzheimer's disease treatment can improve the treatment effect
of mice.
Image source: 123RF
And what exactly are these immune cells that exist around the brain doing? For better tracking, Kipnis and colleagues defined the immune cells near the blood vessels and pia mater around the brain as parenchymal border macrophages (PBM), which are located just between brain tissue and cerebrospinal fluid, and special protein receptor markers that distinguish them from microglia
.
Based on their observations in mice, the presence of PBM is important for vascular function, and PBM, located near the cerebral arterial tree, regulates the movement of the arteries that drive cerebrospinal fluid flow.
If the function of this part of the immune cells is blocked by drugs, the efficiency of cerebrospinal fluid entering the peripheral vascular space is reduced, resulting in the accumulation of toxic waste in the brain
.
After analyzing Alzheimer's disease model mice, the researchers found that these mice had significantly fewer PBMs and a sharp decline in function, they were no longer able to effectively remove waste, and they lost the ability to
regulate blood vessels and cerebrospinal fluid.
In addition to mice, the researchers also retrospectively analyzed PBM changes with the help of data from past studies of Alzheimer's disease patients' tissues, and they clearly saw that the gene expression pattern of PBM in the brains of patients became very disordered compared with healthy people, especially the gene expression related to phagocytosis and endocytosis was very abnormal
.
"Impaired cerebrospinal fluid flow is common in many neurodegenerative diseases, and if we can restore CSF flow by enhancing these macrophages, then we can hopefully slow disease progression," said
study lead author Antoine Drieu, PhD.
Studies have pointed out that in addition to the impact of disease, normal human individuals can also experience a decrease in cerebrospinal fluid mobility from the age of 50, and elderly mouse models also confirm this trend
.
However, when the authors enhanced the function of macrophages in aged mice with drugs, their PBM re-showed the same as that of young mice, and the waste removal efficiency in the brains of mice was improved
.
"These results suggest that PBM can be a new target for improving brain aging and some diseases, and my colleagues and I are considering how to use them to treat Alzheimer's disease," Professor Kipnis said.
”
Retrieved November 9, 2022 from style="font-size: 10px;color: rgb(178, 178, 178);" _mstmutation="1" _istranslated="1"> [2] Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid.
Nature (2022).
DOI: https://doi.
org/10.
1038/s41586-022-05397-3
