Scientists at Washington University School of Medicine in St. Louis have identified a method to protect brain cells from destruction in mice, offering a new potential path for treating Alzheimer’s disease. The study, published in the journal Neuron, demonstrates that blocking a specific immune signal can reduce brain damage even when the underlying toxic proteins remain.
Targeting the Immune Response
Alzheimer’s disease and related conditions, known as tauopathies, are characterized by the buildup of abnormal tangles of a protein called tau inside the brain. As these tangles accumulate, nearby neurons begin to die. While current treatments focus on removing amyloid plaques, they have not been shown to prevent brain cell death or treat primary tauopathies where tau accumulates without amyloid.
Previous research from the same laboratory showed that T cells, a type of immune cell, enter the brains of mice with abnormal tau accumulation. These cells concentrate in regions with the most tau and contribute to neurodegeneration. The new study investigates the mechanism that guides these harmful cells into the brain.
The team found that activated T cells use a surface receptor called CXCR3 to follow chemical signals known as chemokines. Specifically, they tracked CXCL10, a signal found in high levels in both mice with tau deposits and people with Alzheimer’s disease. When the researchers blocked CXCR3 with an antibody, T cells could not infiltrate the brain.
“In tauopathies, including Alzheimer’s disease, there’s no treatment right now that actually decreases neurodegeneration,” said David M. Holtzman, MD, senior author of the study. “If we can show that we’re really decreasing brain cell death, it’s certainly worth trying to pursue that pathway to prevent the most devastating consequences of these diseases.”
Preserving Brain Tissue Without Removing Tau
The researchers administered the antibody to young mice that already had tau deposits but had not yet experienced substantial loss of brain cells. They gave the treatment once every five days for three and a half months. The results showed a significant reduction in brain damage.
Treated mice had approximately half as many T cells in their brains as untreated animals. They also retained roughly 40% more tissue in brain regions involved in memory and performed better on memory tests. Crucially, these improvements occurred even though the amount of accumulated tau remained unchanged.
The antibody reached the boundary of the brain but did not enter the brain tissue itself. This suggests that it may be possible to reduce neurodegeneration by targeting immune activity from outside the brain. Such an approach could avoid one of the major difficulties in developing neurological treatments: getting drugs across the blood-brain barrier.
“For this therapeutic approach, if it is safe, you wouldn’t have to design the drug to get into the brain — which is a big deal since most molecules don’t cross the blood-brain barrier well — and you don’t have to get rid of the tau to get this therapeutic effect,” Holtzman said.
The findings suggest that medications already used to control T cells in other diseases, such as multiple sclerosis, might be worth investigating for their potential to reduce Alzheimer’s-related brain damage. This would represent a significant shift in treatment strategy, moving away from exclusively targeting abnormal proteins to also addressing the immune responses that contribute to neuronal destruction.
Source: ScienceDaily
