MGH Studies Shed Light on Alzheimer’s Development and Potential Treatments
Researchers are learning more about how certain immune cells and hormones affect the course of Alzheimer’s disease.
Two recent Massachusetts General Hospital (MGH) studies have revealed more about the factors that contribute to the development and progression of Alzheimer’s disease, as well as those that may help to prevent or delay onset of the condition.
In one study, published in the journal Neuron, MGH researchers found that the exercise-induced muscle hormone irisin helps reduce levels of amyloid beta, a protein that is a hallmark of Alzheimer’s disease when it forms plaques between brain cells and disrupts their function. Another component of Alzheimer’s is the formation of tau protein tangles inside neurons, destroying the brain cells from within. Research has shown that exercise triggers muscles to secrete irisin, which can have a protective effect on multiple organs, including the brain.
The impact of amyloid plaques and tau tangles was at the heart of a separate study, published in the journal Nature Neuroscience. The accumulation of these toxic proteins triggers the body’s immune response, which then causes inflammation in the brain (neuroinflammation). For the study, MGH researchers used a newly developed 3D human cellular model to demonstrate how certain immune cells—called CT8+ T cells— surge into the brain in response to the death of neurons caused by Alzheimer’s disease. The increase of these immune cells in the brain amplifies the harmful effects of neuroinflammation.
“This multidisciplinary research approach identified the different behaviors of distinct cell types in this disease context, and aimed to shed light on the underlying mechanisms to identify strategies for intervention that could lead to more effective treatments,” says the study’s co-lead author and MGH neurologist Joseph Park, PhD.
T Cells and Alzheimer’s
Delivering drugs directly to brain tissue can be challenging, as many substances cannot cross the blood-brain barrier, a shield of sorts that helps prevent toxic substances from reaching the brain and filters certain compounds from the brain to the bloodstream. The blood-brain barrier also allows certain nutrients to reach brain tissue. While some drugs can cross the blood-brain barrier, most drugs and chemicals cannot.
But MGH researchers are encouraged that targeting the T cells in their study may be a way to deliver medications to brain tissue affected by Alzheimer’s disease. T cells are actually a type of white blood cell called lymphocytes. They play important roles in the immune system, fighting pathogens such as bacteria and viruses.
Unfortunately, when T cells are dispatched to the brain to combat amyloid and tau buildup, they can accumulate in such high numbers that they wind up exacerbating the inflammatory response in the brain and fueling the progression of Alzheimer’s disease.
But in their research, scientists identified a pathway between a chemokine(CXCl10) and a chemokine receptor (CXCR3) that is instrumental in regulating T cell infiltration of the brain. Chemokines are a kind of cytokine, which are proteins that help control inflammation in the body. Receptors are proteins on or within certain cells that receive signals to carry out various tasks.
Researchers suggest that blocking the pathway between CXCL10 and CXCR3 appeared to prevent T cell infiltration and neurodegeneration in Alzheimer’s disease laboratory cultures. “Perhaps what is most exciting about this study is that we have identified a new drug target on T cells outside of the brain, which would be more accessible to novel treatments, especially since it has been traditionally difficult to get drugs into the brain,” says senior study author Rudolph Tanzi, PhD, director of MGH’s Genetics and Aging Research Unit.
Irisin and Amyloid
Dr. Tanzi was also senior author of the study published in Neuron, which suggests that irisin-based therapies may help fight the progression of Alzheimer’s disease. He and his research team found that irisin triggers brain cells called astrocytes to increase production of neprilysin, an enzyme that degrades amyloid in the brain.
“Our findings indicate that irisin is a major mediator of exercise-induced increases in neprilysin levels leading to a reduced amyloid beta burden, suggesting a new target pathway for therapies aimed at the prevention and treatment of Alzheimer’s disease,”Dr. Tanzi says.
Future areas of study may explore whether it might be possible to artificially (without exercise) boost irisin and/or neprilysin levels with medications or other therapies.
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