Cholesterol and beta-amyloid
Cholesterol regulates the formation of amyloid plaques in Alzheimer's disease
One of the characteristic signs of Alzheimer's disease, a common cause of senile dementia, is the accumulation of the pathological beta-amyloid protein in the brain tissues. Recently, scientists have confirmed the participation in this process of a well–known fat-like organic substance - cholesterol. But how to apply this knowledge in practice is unclear.
The word "cholesterol" has become almost a curse word for many people, primarily striving for a healthy lifestyle. In many ways, this happened thanks to the statements of the WHO, which declared cholesterol almost the main cause of the appearance of the "silent killer" of atherosclerosis.
In fact, this compound is not only the most important building block of all animal cell membranes, but also a real "multi-cell". Thus, cholesterol serves as a precursor to steroid hormones, including sex hormones, and bile acids, which are necessary for digestion; a lot of cholesterol is contained in the nervous tissue, where it performs important functions.
In the cell membrane, cholesterol, along with other specific lipid molecules, is located in special structured areas – the so-called lipid rafts. These sites provide separate localization of proteins and lipids and coordinate a variety of cellular processes occurring in membranes, such as the assembly of signaling molecules, the movement of membrane proteins, etc.
The pathological protein beta-amyloid is one of the main signs of Alzheimer's disease, forms insoluble plaques in the brain of patients. Cholesterol has long been "suspected" of participating in the synthesis and accumulation of this protein, but technological limitations did not allow to study this relationship in detail. Now, to solve this issue, scientists from the United States have used the method of ultra-high resolution microscopy, which allows direct "observation" of biochemical processes in the brain tissues of mice.
Article by Wang et al. Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol is published in the journal PNAS.
As you know, adult neurons do not synthesize cholesterol. This function remains in auxiliary brain cells – astrocytes, which produce cholesterol and transport it to neurons using the apoE protein. Scientists have suggested that with the help of cholesterol, astrocytes regulate the processes in lipid rafts and thus control the accumulation of beta-amyloid in the neuron.
There were grounds for such an assumption. In an earlier study, scientists have already proven the involvement of cholesterol in the work of a number of anesthetics used for general anesthesia. It was cholesterol that turned out to be a direct intermediary in the membrane-mediated mechanism of action of these drugs, expressed in the separation of the enzyme and its substrate.
To test their findings, the researchers conducted a series of experiments on genetically engineered mice with excessive production of beta-amyloid, an animal model of Alzheimer's disease. When cholesterol synthesis was "turned off" in the astrocytes of these mice, the level of beta-amyloid production decreased almost to normal, and amyloid plaques practically disappeared.
Disabling cholesterol in astrocytes (right) removes amyloid plaques and phosphorylated tau protein (left, orange clusters) in a mouse model of Alzheimer's disease. A drawing from the Scripps Research Institute Discovery press release highlights the role of brain cholesterol in Alzheimer's – VM.
It turned out that cholesterol in the form of a complex with the apoE transport protein promotes the movement of the beta-amyloid precursor into the lipid rafts of the neuron membrane, where a pathological protein is formed from it. Blocking the flow of cholesterol from astrocytes to neurons leads to the loss of contact of this precursor with lipid rafts, which blocks its further transformations. So it is cholesterol, in fact, that determines how much beta-amyloid will accumulate in the neuron.
Unfortunately, this knowledge does not yet have a direct practical way out. As mentioned above, cholesterol is necessary for the brain for many processes, including the maintenance of cognitive functions, so it will not be possible to simply "turn it off" in humans, as in experimental mice.
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