Signaling molecule could prevent Alzheimer’s disease – Harvard Gazette

New research in humans and mice identifies a particular signaling molecule that can help modify inflammation and the immune system to protect against Alzheimer’s disease. The work, which was led by investigators from Massachusetts General Hospital (MGH), affiliated with Harvard, is published in Nature.

The cognitive decline associated with Alzheimer’s disease develops when neurons begin to die. “Neuron death can be caused by inappropriate immune responses and excessive neuroinflammation – or inflammation of the brain – triggered by high levels of beta-amyloid deposits and tau tangles, two hallmarks of Alzheimer’s disease,” explains the paper’s co-lead author, Filip Swirski, who led the work while he was a senior researcher at the MGH’s Center for Systems Biology.

“Once neurons start to die in increasing amounts, brain cells called microglia and astrocytes – which are normally feeder cells that clean up debris – activate to cause neuroinflammation in an attempt to protect the brain. They are programmed during evolution to eliminate a region of the brain where there is an excess of neuronal cell death, as this may be due to an infection, which must be prevented from spreading, ”explains the co-lead author Rudolph Tanzi, co-director of the McCance Center for Brain Health at the MGH.

In Alzheimer’s disease, neuronal cell death, caused by beta-amyloid deposits and tau tangles, activates this response. “As neuroinflammation ensues, the amount of cell death is at least 10 times greater than that caused by plaques and tangles,” explains Tanzi. “In fact, without the induction of neuroinflammation, there would be no symptoms of dementia. We know this from “resilient” brains, in which there are a lot of plaques and tangles in an individual’s brain, but no symptoms upon death because there was little or no neuroinflammation. Tanzi provides an analogy, noting that beta-amyloid is the “match” that ignites the “brush fires” that spread, but only when this results in an increasing number of “forest fires” by neuroinflammation. activated by microglia and astrocytes that we lose enough. neurons to suffer from cognitive decline and dementia.

This new study in Nature found that a subset of astrocytes are actually trying to put out the fire by releasing a molecule called interleukin-3 (IL-3), which then converts the killer microglial cells back into nurturing and protective cells. which no longer erase neurons. and instead focus on cleaning up beta-amyloid deposits and tau tangles.

“There may be important clinical implications that astrocytes communicate with microglia via IL-3 to educate the microglia and help them reduce the severity of Alzheimer’s disease,” explains Swirski. “We can now think about how to use IL-3 not only to help curb the neuroinflammation that causes most neuronal cell death in Alzheimer’s disease, but also to induce the microglia to take over. again the beneficial task of removing the deposits and tangles that are at the origin of the pathology of Alzheimer’s disease.

“It was surprising to find IL-3 in the brain,” says first author Cameron McAlpine, then an instructor at the Center for Systems Biology. “Our results suggest that communication between astrocytes and microglia, via IL-3, is an important mechanism that prevents Alzheimer’s disease by requiring the microglia to adapt its protective functions. With further study, IL-3 signaling could offer a new therapeutic opportunity to fight neurological diseases. “

Tanzi is Vice President of Neurology and Director of the Genetics and Aging Research Unit at the MGH. Swirski is Director of the Cardiovascular Research Institute and Professor of Medicine (Cardiology) and Molecular and Interventional Diagnostic Radiology at the Icahn School of Medicine at Mount Sinai in New York. McAlpine is Assistant Professor of Medicine (Cardiology) and Neuroscience at the Icahn School of Medicine. Study co-authors include Joseph Park, Ana Griciuc, Eunhee Kim, Se Hoon Choi, PhD, Yoshiko Iwamoto, Máté G. Kiss, Kathleen A. Christie, Claudio Vinegoni, Wolfram C. Poller, John E. Mindur, Christopher T. Chan, Shun He, Henrike Janssen, Lai Ping Wong, Jeffrey Downey, Sumnima Singh, Atsushi Anzai, Florian Kahles, Mehdi Jorfi, Paolo Fumene Feruglio, Ruslan I. Sadreyev, Ralph Weissleder, Benjamin P. Kleinstiver and Matthias Nahrendorf.

The study was funded by the Cure Alzheimer’s Fund, the National Institutes of Health, the Patricia and Scott Eston MGH Fellowship, a Banting Fellowship from the Canadian Institutes of Health Research, and an individual Kirschstein National Research Service Award undergraduate fellowship.