IS IT POSSIBLE TO REJUVENATE THE CLEANSING MECHANISM OF THE BRAIN AS WE AGE?

Posted October 6, 2019

Blood carries the cells that transport oxygen, fight infectious diseases, and carry messenger molecules and information across organ systems. Dr. Wyss-Coray has set forth an elegant and testable scientific research question:

If we look at how the blood changes during aging, and in diseases like Alzheimer’s, could we learn something about the brain?

The blood contains hormone-like factors that promote growth and survival. The composition of these factors changes in aging and disease. The factors involved in repair, injury, and inflammation increase during aging while those involved in the maintenance and development of tissue decrease with age. In a series of experiments, Dr. Wyss-Coray’s laboratory took blood samples from 295 individuals and measured the levels of more than 100 proteins that were detectable in the blood. The goal of the experiment was to uncover a profile of proteins that characterized aging – the protein signature. The results of the study revealed 9 factors that correlated with aging. Forty-four of these factors significantly changed between the first group of individuals, who were ages 20 – 44 years old, and the second group ages 75-88. Using statistical and bioinformatic programs, the researchers used the data to determine the factors that were best able to predict the age of a person.

This study suggests that the composition of circulating blood present in a younger individual is very different from an older person.

Dr. Wyss-Coray has used bioinformatics to identify outliers in his study. These individuals are people who are over age 70, and yet, the composition of their blood is much more similar to younger people. His lab is trying to understand whether or not these individuals have a decreased likelihood of developing the disease. These early studies presented correlational data. What truly has distinguished Dr. Wyss-Coray’s research has been the follow-up, mechanistic experiments.

Modulators of Brain Aging

In an experiment that gripped the attention of the neuroscience community, it was uncovered that exposure to blood from a young mouse caused the older mouse to resemble a younger mouse. Specifically, the older mouse had less inflammation in the brain, higher activation of the genes involved in memory, higher activity of neurons, and an increase in the birth of neural stem cells. Exposure to this “young blood” resulted in improvement in performance on learning and memory tests in the aging mice. This pioneering research suggested that the brain exhibits plasticity and is capable of being modulated during aging.

New Research from the Wyss-Coray Lab

An open question in the Alzheimer’s field is whether or not the increased activation of microglia observed in Alzheimer’s patients plays a protective role or if the activation is exacerbating the progression of the disease.

Microglia is a cell type in the brain that detects abnormalities and then engulfs and degrades the unwanted material in a process known as phagocytosis. Dr. Wyss-Coray’s laboratory uses sophisticated bioinformatics tools to zero in on the specific factors that can restore aging microglial cells to their former powerhouse level of function. Of the thousands of potential targets, Dr. Wyss-Coray has identified a promising factor that has the potential to revitalize microglia function: inhibiting CD22.

In a pre-clinical research study published in NATURE, with support from Cure Alzheimer’s Fund, Dr. Wyss-Coray’s team of research scientists uncovered a role for CD22, a B-cell receptor, in regulating the phagocytosis process. Microglia help maintain homeostasis in the nervous system by clearing protein aggregates and cellular debris. Phagocytosis declines with age and is seen in neurodegenerative diseases such as Alzheimer’s disease. Using an antibody that blocked the function of CD22 in mice, the researchers were able to enhance phagocytosis. Importantly, the cognitive skills of the aged mice receiving the CD22 blocker, and not the control mice, demonstrated a significant improvement in their cognitive function.

In an interview on Alz Forum, Cure Alzheimer’s Fund investigator Dr. Marco Colonna explained: “It is remarkable that administration of a CD22 blocker in the brains of aged mice boosts the phagocytic function of microglia. Microglia could more efficiently remove both cellular debris and amyloid-beta aggregates injected into the mouse brain. These findings may soon pave the way for applications in humans, especially for the treatment of age-related diseases such as Alzheimer’s.”

Implications for the Research

The ultimate goal of Dr. Wyss-Coray’s research is to understand the cellular changes that occur with aging and to use the knowledge gained from basic science to alter the cellular abnormalities that lead to neurodegeneration.

To find out more about these research studies, please see the research at NATURE and NATURE MEDICINE.

CD22 blockade restores homeostatic microglial phagocytosis in the aging brain

https://www.nature.com/articles/s41586-019-1088-4

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