Nature stops aging – strengthens immune cells and improves brain waste removal

Many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by the presence of harmful protein clusters
in the brain.
Although significant efforts have been made to find cures for these diseases by eliminating these toxic populations, progress has been limited
.

Researchers at Washington University School of Medicine in St.
Louis have discovered a new way to improve brain waste removal, which could lead to the treatment or prevention
of neurodegenerative diseases.
They found that immune cells around the brain play an important role in waste removal efficiency, and these immune cells were impaired
in old mice, humans, and mice with Alzheimer's disease.
In addition, they found that treating aged mice with an immune-stimulating compound rejuvenated these immune cells and improved waste removal
from the brain.

The findings, recently published in the journal Nature, propose a new way
to stop the effects of aging on the brain.

Senior author Dr Jonathan Kipnis said: "Alzheimer's has been studied for many years in terms of how neurons die, but there are other cells, such as immune cells on the periphery of the brain, that may also play a role
in Alzheimer's.
It seems unlikely that dead or dying neurons will be resurrected, but immune cells located at the edge of the brain are viable targets for treating age-related brain diseases
.
They are more readily available and can be medicated or replaced
.
In this study, we treated aged mice with a molecule that activates senescent immune cells, which plays a role
in improving brain fluid flow and waste removal.
This promises to be a treatment
for neurodegenerative diseases.
”

Kipnis is an expert in the field of neuroimmunology, which studies how the immune system affects the brain
in health and disease.
In 2015, he discovered a network of blood vessels that drains fluids, immune cells and small molecules from the brain into the lymph nodes
where many immune system cells are located.
Last year, he and his colleagues demonstrated that some investigational Alzheimer's therapies were more effective
in mice when paired with a treatment designed to improve fluid and debris excretion.

In this study, Kipnis and Antoine Drieu, PhD, a postdoctoral researcher and lead author of the paper, set out to understand the role
played by immune cells that live in the brain's vasculature and light matinges (tissues immediately adjacent to the brain and spinal cord).
They called these cells parenchymal boundary macrophages because they are located at the interface
between cerebrospinal fluid and brain tissue.

In mice studies, Kipnis, Drieu and colleagues found that the macrophages regulate the movement of arteries, which in turn controls the clean flow
of fluid through the brain.
When these macrophages are depleted or damaged, debris builds up in the brain
.

"Cerebrospinal fluid flow is impaired in many neurodegenerative diseases, such as Alzheimer's, stroke, Parkinson's and multiple sclerosis
," Drieu said.
If we can restore fluid flow in the brain by boosting these macrophages, maybe we can slow the progression of
these diseases.
It's a dream, but who knows? May be useful
.
”

Further investigation revealed that the parenchymal boundary macrophages of Alzheimer's patients and mice with Alzheimer's disease-like disease were altered: immune cells had a reduced ability to consume and process waste products and were unable to regulate fluid flow
efficiently.

From about age 50, as part of normal aging, people begin to experience a decline
in cerebral fluid flow.
The same thing happens with
older mice.
Kipnis, Drieu and his colleagues found that in aged mice, there were few
border macrophages that were most important for waste removal and fluid flow.
When they treated the old mice with a protein that boosted macrophage activity, the marginal macrophages began to behave more like the macrophages
of the younger mice.
In addition, this treatment improved fluid flow and waste removal
in the mouse brains.

"Overall, our findings suggest that parenchymal boundary macrophages may be pharmacologically targeted to alleviate brain clearance deficits associated with aging and Alzheimer's disease," said Kipnis, who is also a professor of
neurology, neuroscience and neurosurgery.
"I'm talking with my colleagues about how to replace or restore these cells in an aging brain and as a treatment
for Alzheimer's disease.
" I hope that one day we will be able to slow or delay the development of
age-related brain diseases through this approach.
”

Reference: "Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid" by Antoine Drieu, Siling Du, Steffen E.
Storck, Justin Rustenhoven, Zachary Papadopoulos, Taitea Dykstra, Fenghe Zhong, Kyungdeok Kim, Susan Blackburn, Tornike Mamuladze, Oscar Harari, Celeste M.
Karch, Randall J.
Bateman, Richard Perrin, Martin Farlow, Jasmeer Chhatwal, Dominantly Inherited Alzheimer Network, Song Hu, Gwendalyn J.
Randolph, Igor Smirnov and Jonathan Kipnis, 9 November 2022, Nature.