Will prostaglandin receptor blockers help with Alzheimer's disease?
A retaliatory blow to neurodegeneration
Nanonews Network based on materials from Stanford University School of Medicine:
Blocking receptor in brain’s immune cells counters Alzheimer’s in mice, study findsBrain cells called microglia destroy toxic substances and the remains of dead cells, suppress inflammation and synthesize substances necessary for neurons.
A new study shows that by maintaining their normal function, neurodegeneration can be prevented.
The mass death of nerve cells in the brain of people suffering from Alzheimer's disease may largely be due to the weakening of the function of a completely different class of brain cells called microglia, according to scientists at the Stanford University School of Medicine.
In experiments on mice, researchers have found that suppressing the activity of one of the molecules on the surface of microglial cells restores their ability to properly perform their work and reverses memory loss and many other cognitive impairments characteristic of Alzheimer's disease.
A study published in The Journal of Clinical Investigation (Johansson et al., Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models) shows the importance of microglia and may lead to new ways to prevent Alzheimer's disease, which is projected to affect 15 million people by mid-century, unless any method of its treatment or prevention has been found. In addition, this work may help to find an explanation for the intriguing link between aspirin and a decrease in the rate of development of Alzheimer's disease.
Microglial cells, which make up about 10-15 percent of all brain cells, are actually much closer to immune cells than to neurons.
"Microglia cells are the patrol policemen of the brain," says Katrin Andreasson, MD, professor of the Department of Neurology and Neurological Sciences, head of the study. "Our experiments show that not allowing them to turn off the right path means to counteract memory loss and preserve a healthy physiology of the brain."
A microglial cell is a sentry on the front line, tracking suspicious activity in its area of responsibility by probing the surrounding microenvironment. Seeing a violation, it releases substances that attract other microglial cells, explains Professor Andreasson. These cells are tough policemen protecting the brain from invading bacteria and viruses. In addition, they are experts in "calming", suppressing inflammation if it gets out of control. In addition, they work as "garbage collectors" – they destroy dead cells and molecular waste scattered among living cells, including clusters of beta-amyloid protein, known for its ability to form sticky aggregates. Such aggregates, called beta-amyloid plaques, are a characteristic anatomical feature of Alzheimer's disease.
Beta-amyloid, synthesized throughout the body, is as natural as it is ubiquitous. But when it gathers into soluble clusters consisting of several molecules, its extremely high neuronal toxicity manifests itself. These clusters are believed to play a significant role in the onset of Alzheimer's disease.
"Microglial cells must, first of all, constantly remove beta-amyloid, and also keep inflammation in check," explains Professor Andreasson. "If they lose the ability to function, the situation gets out of control: beta-amyloid accumulates in the brain, causing toxic inflammation."
Professor Andreasson and her colleagues have received convincing evidence that this microglial dysfunction is caused, to a large extent, by increased signaling activity of one of the molecules on the surface of microglial and nerve cells. Previous work by Andreasson's lab has shown that this molecule, the EP2 receptor protein, has great potential to cause inflammation when activated by prostaglandin E2, or PGE2.
Researchers have already observed that in bioengineered mice whose brain cells are deprived of this receptor, the activity of the inflammatory process in the brain is significantly reduced. But they didn't know which cells were responsible for this inflammatory activity – neurons or microglia–and what its specific consequences were, and decided to find out.
The experiments began in a Petri dish. It is quite difficult to isolate viable microglia cells from the brain, while it is much easier to collect a large number of their close relatives – immune cells called macrophages. Macrophages circulate throughout the body and are easily obtained from a blood sample. Not being copies of each other, microglial cells and macrophages share many common genetic, biochemical and behavioral characteristics.
Placed in a Petri dish with soluble beta-amyloid clusters, the macrophages of young mice responded calmly, synthesizing recruiting chemicals and not increasing the production of inflammatory molecules. It should be noted that these young cells actively produced beta-amyloid-destroying enzymes. A different picture was observed in experiments with macrophages of old mice: in these cells, the presence of beta-amyloid provoked a significant increase in the activity of EP2, which, ultimately, was expressed in the enhanced synthesis of inflammatory molecules and a decrease in the production of recruiting chemicals and beta-amyloid-destroying enzymes.
Diagram from an article in J Clin Invest – VM
This is the first indication that an age-related change in the activity of the EP2 receptor of microglial cells may contribute to the development of some of the neuropathological manifestations directly related to Alzheimer's disease was confirmed in subsequent experiments in which mice genetically predisposed to the development of an analogue of Alzheimer's disease were used, as well as normal mice into whose brains scientists injected either beta-amyloid or a control solution. The expected negative effect on memory and learning ability was not manifested in any of the two groups of mice if, as a result of genetic manipulation, EP2 was absent on microglial cells. Suppression of the activity of EP2 microglial receptors significantly improved the results shown by animals in two types of standard memory tests (one of the tests assessed how quickly mice forget that they have already encountered an object before; the other - the ability to remember the location of a food reward in the maze).
In mice with excessive amounts of beta-amyloid, either accumulating gradually (mice with "Alzheimer's"), or appearing suddenly (mice with injections into the brain), and beta-amyloid-activated microglia, knockout of EP2 function obviously improved memory. In addition, when provoking the brain with beta-amyloid, the microglia of bioengineered mice devoid of EP2 significantly surpassed the unchanged microglia in performing such important tasks as the secretion of recruiting chemicals and factors beneficial to nerve cells, and the synthesis of proteins that counteract rather than stimulate inflammation.
Epidemiological reports suggest that nonsteroidal anti-inflammatory drugs, such as aspirin, can prevent the development of Alzheimer's disease, although only if their intake begins long before any signs of the disease appear in older people, says Andreasson.
"If you have even the slightest hint of memory loss, these drugs will have no effect," the scientist emphasizes.
NSAIDs mainly work by blocking two enzymes – COX-1 and COX-2. These enzymes create a molecule that can be converted into several different substances, including PGE2, a hormone–like substance that triggers the activation of EP2.
Although PGE2 is known to regulate inflammatory changes in the brain, it performs various functions in many tissues of the body – from influencing blood pressure to enabling labor. Further complicating matters is that PGE2 is only one of five different prostaglandins derived from the precursor molecule produced by COX-1 and COX-2. Therefore, aspirin and other COX-1- and COX-2-inhibiting drugs can have countless effects, not all of which are beneficial. According to Professor Andreasson, it may turn out that for protection against Alzheimer's disease without side effects, a compound that suppresses EP2 activity only on microglial cells or targets any underlying consequences of EP2 activity is better suited. Her group is already studying the biological mechanisms by which PE2 signaling leads microglia cells astray.
Portal "Eternal youth" http://vechnayamolodost.ru18.12.2014