Alzheimer's disease: another promising approach
The removal of beta-amyloid from the brain is hindered by the absence of an immune cell receptor
LifeSciencesToday based on MGH materials: Lack of immune cell receptor impairs clearance of amyloid beta protein from the brainIncreased expression of Scara1 protein may slow down the progression of Alzheimer's disease
Identification of a protein that appears to play an important role in removing beta-amyloid protein from the brain may lead to a new strategy for the treatment of Alzheimer's disease. An article by scientists from Massachusetts General Hospital (MGH) was published in the journal Nature Communications: Frenkel et al., Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer's-like disease progression.
"We have identified a receptor protein that mediates the excretion of soluble beta-amyloid from the brain by cells of the innate immune system," says associate professor of medicine at Harvard Medical School Joseph El Khoury, MD, from the Center for Immunology and Inflammatory Diseases of the Infectious Diseases Department of MGH, author of the article. "In addition, we found that deficiency of this receptor in a mouse model of Alzheimer's disease leads to increased deposition of beta-amyloid and accelerated death, and its increased expression enhances the excretion of beta-amyloid from the brain."
In the development of neurodegenerative diseases, such as Alzheimer's disease, the immune system of the brain, which includes microglial cells, monocytes and macrophages that absorb and remove foreign substances, apparently plays a dual role. In the early stages, in response to the accumulation of beta-amyloid, the main component of toxic plaques in the brain of patients with this severe neurological disease, the activity of immune cells increases. But as the disease progresses and the size of beta-amyloid plaques increases, the cells not only lose the ability to remove beta-amyloid, but also secrete pro-inflammatory chemicals that aggravate damage to brain tissue.
Mixed culture of rat brain cells. The cells are stained with coronin 1a (coronin 1a), found only in microglia (shown in green), and alpha-internexin (alpha-internexin) (shown in red), involved in neural processes. Photo: EnCor Biotechnology Inc.The study of factors that may underlie the loss of the immune system's ability to remove beta-amyloid led Dr. El Khoury to the hypothesis that, in addition to recognizing and binding the insoluble form of beta-amyloid amyloid plaques, immune brain cells can interact with soluble forms of beta-amyloid that begin to accumulate in the brain before the appearance of plaques.
Scientists began by studying a group of receptor proteins used, as is known, by microglial cells, monocytes and macrophages to interact with insoluble beta-amyloid. Although the role of these proteins in the development of Alzheimer's disease is unknown, MGH scientists have previously found that their expression in a mouse model of this disease decreases with age.
First, the researchers established the participation of the Scara1 receptor in the absorption of soluble beta-amyloid by monocytes and macrophages, and then confirmed that Scara1 is obviously the main receptor for the recognition and removal of beta-amyloid by the innate immune system – the first line of defense of the body. In the mouse model of Alzheimer's disease, animals with the absence of one or both copies of the Scara1 gene died several months earlier than those with two functional copies of this gene. In eight-month-old mice with an Alzheimer's disease model that did not have functional Scara1 genes, the amount of beta-amyloid in the brain was twice as much as in animals with this disease that made up the control group; in the brains of normal mice, beta-amyloid was practically absent.
To explore the possible therapeutic use of Scara1 to remove beta-amyloid, the researchers treated immune cell culture with Protollin, an adjuvant used to enhance the immune response to certain vaccines. Treatment of immune cells with Protollin caused a threefold increase in the expression of Scara1, as well as an increase in the level of one of the proteins that attracts other immune cells. The addition of protollin-activated microglial cells to the brain samples of mice with Alzheimer's disease reduced the size and amount of beta–amyloid deposits in the hippocampus – an area particularly damaged by this disease - but this decrease was significantly less if microglial cells were taken from Scara1-deficient animals.
The fact that Protollin treatment reduces the amount of beta-amyloid deposits in mice with Alzheimer's disease has been shown in other studies; Dr. El Khoury's experiments reveal a probable molecular mechanism of this effect.
"Increasing the expression of Scara1 is a promising approach to the treatment of Alzheimer's disease," the scientist believes. "Now we have to duplicate these experiments using human cells and identify new classes of molecules that can painlessly increase the expression or activity of Scara1. This could potentially lead to the development of methods to use the immune system to delay the progression of the disease."
Portal "Eternal youth" http://vechnayamolodost.ru09.07.2013