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September each year is the "World Alzheimer's Disease Month" advocated by the International Alzheimer's Disease Association (ADI). According to ADI's report, every 3 seconds, there will be one more patient in the world in Alzheimer's disease (AD). This disease will gradually cause patients to lose their memories of the past few decades and move towards the end of their lives "silently".
Image source: 123RF
On the other hand, there is no cure for this neurodegenerative disease. The new drugs that many pharmaceutical companies spent more than ten years developing for AD were almost wiped out.
The heavy burden of disease has prompted scientists to constantly find new ways to overcome AD. A scientific research team led by Professor Du Heng of the University of Texas at Dallas in the United States has brought a possible treatment strategy based on the analysis of patient and animal models. They found that 's resistance to "ghrelin" is related to memory loss and cognitive impairment in AD. " Science " sub-issue Science Translational Medicine recently introduced this result with a cover article.
So, what is "grenin"? From a literal sense, it is related to "hunger", so why is it related to AD?
This is a hormone produced in the stomach that signals the brain to regulate energy balance and weight. It does promote appetite, but interestingly, related research shows that this hormone may also be related to learning and memory.
There is a brain area called hippocampus in the brain, which is crucial for learning, memory and emotions, and is also one of the first areas that AD attacks. A toxic protein called amyloid beta builds up in the hippocampus, causing nerve cell death, which is considered an early symptom of AD.
In a healthy hippocampus, ghrelin binds to its receptor GHSR1α, which in turn combines with the dopamine-activated receptor (DRD1), forming a protein complex that helps brain cells communicate and ultimately maintain memory.
▲Director Jing Tian, Professor Lan Guo and Professor Du Heng (Photo source: UTD official website)
analyzed brain tissue samples after death of AD patients. Professor Du Heng and colleagues observed that amyloid beta binds to the ghrelin receptor in the hippocampus. Experiments in AD mouse model further confirmed that after the ghrelin receptor was "hijacked" by beta amyloid protein, it could not be combined with the dopamine receptor , resulting in the loss of synaptic connections between nerves and the damage to memory.
This situation reminds researchers of the familiar diabetes. Due to the resistance of insulin , the compensation effect causes early-stage type II diabetes patients to produce more insulin to bind to insulin receptor . However, no matter how much insulin the body produces, the insulin receptor is difficult to activate downstream biochemical reactions and send glucose in the blood into cells.
Similarly, in the brain of AD patients, since amyloid beta binds to ghrelin receptors, no matter how much the body increases ghrelin and increases the amount of GHSR1α in the brain, these receptors cannot perform their functions. "Based on our findings, AD may be related to ghretin resistance," said Professor Du.
▲ In the hippocampus of AD patients, amyloid deposition binds to ghrelin receptors (Image source: Reference [1])
This new discovery also gives a reasonable explanation for a recent clinical trial that has been stagnant. In this clinical trial, the researchers used a compound called MK0677 to try to activate GHSR1α in the brain, but the results showed that MK0677 could not slow the progression of AD.
"Our hypothesis is that the isolation of ghrelin receptor and dopamine receptor may be the reason for affecting the cognition of AD patients ." To verify this conjecture, researchers from Du Heng's team injected the AD mouse model with MK0677 and another compound that activates dopamine receptors.
As expected, when the ghrelin receptor is protected and the dopamine receptor is enhanced, it can promote the formation of a complex between the two receptors.Sure enough! After the injection of the two drugs at the same time, the cognition and memory of AD mice were improved, and the connection between hippocampus nerve cells was enhanced, and the lesions were reduced. "The key is to activate both receptors at the same time!" Professor Du said.
▲The use of agonists of both receptors at the same time significantly enhanced the synapses in the brain of AD mice (Image source: Reference [1])
"This requires more research, but the idea for this mechanism may be proved to have therapeutic effects." It is reported that Professor Du has applied for a patent for this method.
This discovery also gives us a new understanding of aging. "As we age, our body's metabolism often changes. These changes will affect the heart and stomach, but may also affect the brain by changing GHSR1α." Dr. Du Heng said: "We know that even without AD, many elderly people have memory problems, which may be related to the separation between receptors in the brain, even without amyloid."
looks forward to scientists ushering in a new breakthrough as soon as possible, so that everyone can age healthy with full life memories.
References:
[1] Jing Tian et al., (2019) Disrupted hippocampal growth hormone secretagogue receptor 1α interaction with dopamine receptor D1 plays a role in Alzheimer’s disease. Science Translational Medicine, doi:10.1126/scitranslmed.aav6278
[2] World Alzheimer Report 2018. Retrieved Sep 5th 2019 from https://www.alz.co.uk/research/world-report-2018
[3] Scientists Link ‘Hunger Hormone’ to Memory in Alzheimer’s Study. Retrieved Sep 5th 2019 from https://www.utdallas.edu/news/research/hunger-hormone-memory-alzheimers-2019/?WT.mc_id=NewsHomePageCenterColumn
[4] Study of MK0677 for the Treatment of Alzheimer's Disease (0677-030)(COMPLETED). Retrieved Sep. 7, 2019, from https://clinicaltrials.gov/ct2/show/NCT00074529
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