Revitalized immune cells improve waste removal from the brain

Damaged protein clusters in the brain are a hallmark of many neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and others. Although they have made significant efforts, scientists have only partially succeeded in finding treatments for these conditions by removing these toxic clusters.

Now, scientists at Washington University School of Medicine in St. Louis have discovered an innovative method to improve waste clearance from the brain, potentially treating or even preventing neurodegenerative diseases.

They demonstrated that the immune cells that surround the brain have an impact on how effectively waste is removed from the brain and that these immune cells are impaired in old mice, in humans, and in mice with Alzheimer’s disease.

Furthermore, they discovered that administering an immune-stimulating compound to old mice rejuvenates immune cells and enhances waste removal from the brain.

The study, which was released on November 9^th, 2022, in Nature, provides a new strategy for slowing down some of the negative effects of aging on the brain.

Alzheimer’s has been studied for many years from the perspective of how neurons die, but there are other cells, such as immune cells on the periphery of the brain, that also may play a role in Alzheimer’s.”

Jonathan Kipnis PhD, Study Senior Author and Alan A. and Edith L. Wolff Distinguished Professor, Pathology and Immunology, Washington University School of Medicine in St. Louis

He added, “It does not look likely that we will be able to revive dead or dying neurons, but the immune cells that sit on the borders of the brain are a feasible target for treating age-related brain diseases. They are more accessible, and could be drugged or replaced.”

“In this study, we treated aged mice with a molecule that can activate aged immune cells, and it worked in improving fluid flow and waste clearance from the brain. This holds promise as an approach to treating neurodegenerative diseases,” stated Kipnis.

Kipnis is a specialist in neuroimmunology, a rapidly expanding field that examines how the immune system affects the brain in both health and disease. He discovered in 2015 a network of vessels that transports fluid, immune cells, and small molecules from the brain into the lymph nodes, which are home to many immune system cells.

He and his coworkers demonstrated last year that certain experimental Alzheimer’s therapies work better in mice when combined with a regimen designed to enhance the removal of fluid and debris from the brain.

In this study, Kipnis and Antoine Drieu, PhD, a postdoctoral researcher and the study’s lead author, sought to comprehend the function of immune cells that reside in the leptomeninges, the tissues that cover the brain and spinal cord, and along the brain’s vasculature.

The fact that these cells are located at the boundary between brain tissue and cerebrospinal fluid led researchers to name them parenchymal border macrophages.

Through the study of mice, Kipnis, Drieu, and colleagues found that these macrophages control the movement of blood vessels, which in turn regulates the aqueous fluid flow through the brain that is cleansing. Debris accumulated in the brain when these macrophages were insufficient or ineffective.

Cerebrospinal fluid flow is impaired in numerous neurodegenerative diseases, such as Alzheimer’s, stroke, Parkinson’s and multiple sclerosis. If we can restore fluid flow through the brain just by boosting these macrophages, maybe we can slow the progression of these diseases. It is a dream, but who knows? It might work.”

Antoine Drieu PhD, Study Lead Author and Postdoctoral Researcher, Washington University School of Medicine in St. Louis

Further research showed that parenchymal border macrophages are modified in humans with Alzheimer’s disease and in mice with an Alzheimer’s-like condition: The immune cells are less capable of consuming and eliminating waste and cannot effectively control fluid flow.

People begin to experience a decrease in brain fluid flow around the age of 50 as a natural part of aging. In older mice, the same thing takes place. The type of border macrophage that is crucial for waste clearance and fluid flow is rare in older mice, according to research by Kipnis, Drieu, and colleagues.

Old mice were given a protein that increases macrophage activity, and the border macrophages began acting more like those from younger mice as a result. In addition, the treatment enhanced waste removal from the mice’s brains and fluid flow.

Kipnis stated, “Collectively, our results show that parenchymal border macrophages could potentially be targeted pharmacologically to alleviate brain clearance deficits associated with aging and Alzheimer’s disease.”

He further added, “I am discussing with colleagues how we can replace or rejuvenate those cells in aging brains and as a treatment for Alzheimer’s. I hope that one day we will be able to slow down or delay the development of age-related brain diseases with this approach.”

Kipnis is the director of a program funded by a $15 million grant from the National Institutes of Health (NIH) to investigate how immune cells such as border macrophages interact with brain fluid flow and drainage to affect aging, in addition to Alzheimer’s disease and cerebral amyloid angiopathy, two degenerative brain conditions.

Finding new treatments for neurodegeneration and dementia brought on by aging is the objective of the program.