Nature: Rejuvenated immune cells do a better job of removing toxic waste from the brain

Alzheimer's, Parkinson's, and many other neurodegenerative diseases are characterized by destructive clusters
of proteins in the brain.
Scientists have spent tremendous efforts to find a cure for the disease by removing these toxic substances, but with limited
success.

Now, researchers at Washington University School of Medicine in St.
Louis have discovered an innovative way to improve waste removal in the brain, potentially treating and even preventing neurodegenerative diseases
.
They showed that immune cells around the brain affect how efficiently waste is removed from the brain, and this immune cell is damaged
in old mice, humans, and mice with Alzheimer's.
In addition, they found that treating old mice with an immune-stimulating compound rejuvenated immune cells and promoted the removal
of brain waste.

The findings, published Nov.
9 in the journal Nature, suggest a new way
to stop the effects of aging on the brain.

Senior author Dr Jonathan Kipnis said: "Alzheimer's disease 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 we will resurrect dead or dying neurons, but immune cells located at the edge of the brain are a viable target
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 aged immune cells, which plays a role
in improving fluid flow and waste removal in the brain.
This promises to be a treatment
for neurodegenerative diseases.
”

Kipnis is an expert in the burgeoning 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 fluid, immune cells and small molecules from the brain to the lymph nodes
where many immune system cells are located.
Last year, he and colleagues demonstrated that some experimental Alzheimer's therapies were more effective
in mice when combined with a treatment designed to improve fluid and debris excretion from the brain.

For the study, Kipnis and Dr.
Antoine Drieu, a postdoctoral researcher and first author of the paper, set out to understand the role
played by immune cells that live in the brain's vascular system and light matinges (tissues that close around the brain and spinal cord).
They called these cells parenchymal boundary macrophages because they sit at the interface
between cerebrospinal fluid and brain tissue.

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

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

Further research showed that the parenchymal boundary macrophages of Alzheimer's patients and mice with Alzheimer's-like disease were altered: immune cells were less able to consume and process waste products and could not effectively regulate fluid flow
.

From around the age of 50, as part of normal aging, people begin to experience a decline
in cerebral fluid flow.
The same thing happened with
older mice.
Kipnis, Drieu and colleagues found that in aged mice, boundary macrophages, which are most important for waste removal and fluid flow
, are scarce.
When they treated the old mice with a protein that enhanced macrophage activity, the marginal macrophages began to behave more like the macrophages
of the younger mice.
In addition, the treatment improved fluid flow and waste removal
in the brains of mice.

"Overall, our findings suggest that parenchymal boundary macrophages may be targeted for use to alleviate brain clearance deficits associated with aging and Alzheimer's disease, and I am discussing with colleagues how to replace or restore these cells in aging brains 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.
”

A project led by Kipnis and received a $15 million grant from the National Institutes of Health (NIH) to explore how border macrophages and other immune cells interact with fluid flow and excretion in the brain, leading to aging, as well as Alzheimer's disease and amyloid angiopathy — both brain diseases that cause dementia
.
The goal is to find new treatments
for neurodegeneration and senile dementia.
Co-investigator Gwen Randolph, Ph.
D.
, Emil R.
Unanue Distinguished Professor of Immunology; Marco Colonna, MD, Robert Rock Belliveau Professor of Pathology; and David Holtzman, MD, Barbara Burton, and Reuben M.
morris III Distinguished Professor of Neurology, all of whom are leading projects
in larger initiatives.