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SAN FRANCISCO, CA – February 5, 2019 – It has long been known that patients with Alzheimer's disease have abnormalities in the vast network of blood vessels in the brain. Some of these alterations may also contribute to the cognitive decline badociated with aging in people without dementia. However, the way in which these vascular pathologies contribute to cognitive dysfunction has remained largely a mystery. Until now, that's it.
Scientists from Gladstone institutes, led by lead researcher Katerina Akbadoglou, PhD student, showed for the first time that a blood clotting protein called fibrinogen is responsible for a variety of molecular and biological events. likely to destroy cognitive decline.
Akbadoglou and his team have used advanced imaging technology to study both the mouse brain and the human brain of Alzheimer's disease patients. They also produced the first three-dimensional volume imaging showing that Alzheimer's disease had leaks in the blood-brain barrier.
In their study, published in the scientific journal neuron, the researchers found that fibrinogen, after a leak of blood in the brain, activates the immune cells of the brain and causes them to destroy important connections between neurons. These connections, called synapses, are essential for neurons to communicate with each other.
Previous studies have shown that the elimination of synapses leads to memory loss, a common feature of Alzheimer's disease and other dementias. Indeed, scientists have shown that preventing fibrinogen from activating immune cells in the brain protected murine models of Alzheimer's disease from memory loss.
"We found that blood leaks into the brain could result in the elimination of neuronal connections important to memory functions," says Akbadoglou, professor of neurology at UC San Francisco (UCSF). "This could change the way we think about the cause and possible treatment of cognitive decline of Alzheimer's disease and other neurological diseases."
The team showed that fibrinogen can have this effect even in brains lacking amyloid plaques, which are the subject of various treatment strategies and have failed in large-scale clinical trials. The researchers showed that injecting even very small amounts of fibrinogen into a healthy brain resulted in the same type of immune cell activation and loss of synapses as that seen in the disease. ; Alzheimer's.
"Traditionally, the formation of amyloid plaques in the brain was thought to be the cause of memory loss and cognitive decline of Alzheimer's disease," said Mario Merlini, first author of the study and researcher Principal at the Akbadoglou laboratory at Gladstone. "Our work identifies another culprit who could be responsible for the destruction of the synapses."
The scientists' data help explain the findings of recent human studies, in which elderly people with vascular pathology had similar rates of cognitive decline to those of the same age with a medical condition. l & # 39; amyloid. However, patients with both types of pathology had much more severe and rapid cognitive decline. Other studies have also identified vascular pathology as a powerful predictor of cognitive decline that may act independently of amyloid pathology.
"Given the human data showing that vascular changes are early and complementary to amyloid, these studies conclude that vascular changes may need to be targeted with separate treatments if we want to provide maximum protection against the destruction of neuronal connections leading to cognitive impairment, decline, "says Akbadoglou.
Akbadoglou and his colleagues recently developed an antibody that blocks the interaction between fibrinogen and a molecule of immune cells in the brain. In a previous study, they had shown that this antibody protected mouse models of Alzheimer's disease against brain inflammation and neuronal damage.
"These exciting discoveries dramatically improve our understanding of the contributions of vascular pathology and brain inflammation to the progression of Alzheimer's disease," said Lennart Mucke, MD, co-author of the report. study and director of the Gladstone Institute of Neurological Disease. "The mechanisms identified by our study may also play a role in a series of other diseases that badociate leakage in the blood-brain barrier to neurological decline, including multiple sclerosis, traumatic brain injury and stroke." Chronic traumatic encephalopathy and its therapeutic implications are considerable. "
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About the study
The paper "Fibrinogen Induces Microglial-mediated Spine Elimination and Cognitive Impairment in a Model of Alzheimer's Disease" was published by the journal neuron February 5, 2019: https://www.cell.com/neuron/fulltext/S0896-6273(18)31051-1.
Other authors include Victoria A. Rafalski, Pamela E. Rios Coronado, T. Michael Gill, Maya Ellisman, Gayathri Muthukumar, Keshav S. Subramanian, Jae Kyu Ryu, Catriona A. Syme and Dimitrios Davalos of Gladstone, as well as William W. Seeley of UCSF and Robert B. Nelson of Lundbeck Research USA.
The work was supported by the National Institute of Neurological Disorders and Disorders, the Swiss National Science Foundation, the Run to Clear MS, the American Heart Association, the Ray Family Fund and Dagmar Dolby, H. Lundbeck A / S and the Conrad N Hilton Foundation.
About Gladstone Institutes
In order for our work to produce the greatest possible benefit, the Gladstone Institutes focus on conditions with significant medical, economic and social impact – unresolved diseases. Gladstone is an independent, not-for-profit life science research organization that uses visionary science and technology to defeat disease. He has an academic affiliation with the University of California San Francisco.
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