September 21st is the 24th World Dementia Day, a disease that has severely devastated the body and mind of the elderly. Once suffering from dementia, all the memory in the patient's brain will begin to be erased. Even the former US President Ronald Reagan and former British Prime Minister Margaret Thatcher failed to escape this bad luck.
Alzheimer's disease (AD) occurs in 50% to 80% of cases of dementia. Its pathological feature is that a large amount of β-amyloid (Aβ) deposits in the brain of patients to form brown patches. As the neurons that control memory and thinking continue to die, cognitive ability gradually declines, and finally they lose consciousness and cannot take care of themselves.
So, what is the real “culprit” of dementia? And why global trials of new drugs for Alzheimer's disease failed repeatedly in recent years? To figure out the reason, please just move on reading.
The efficacy of new drugs is short-lived
In the 1990s, the global major pharmaceutical companies recognized Aβ as the cause of AD, although "Aβ-induced AD" was still an unconfirmed hypothesis. They hypothesized that if anti-Aβ antibodies are injected into AD patients, then these antibodies can circulate into the brain along the bloodstream, sweeping away Aβ as “garbage”. As a result, these pharmaceutical companies have invested heavily in the development of antibody drugs for many years, hoping to ease or even cure AD with this application.
Subsequently, various anti-Aβ antibody drugs have been developed, and tests have been carried out in terms of efficacy in experimental animals such as mice. After several years of preclinical testing, the researchers found that some antibody drugs do have a good effect, and further human trials are needed for safety and efficacy evaluation.
According to Nature issued on July 30, 2015, the US pharmaceutical giant Eli Lilly previously recruited 440 subjects to launch a phase III clinical trial of anti-Aβ monoclonal antibody solanezumab. The monoclonal antibody was developed by the team of neurobiologists Samuel Gandhi of Mount Sinai School of Medicine in New York City, USA, and is a product of Washington Biogen. Clinical evaluation data showed that solanezumab can delay cognitive decline in patients with mild AD, with a significant rate of 34%. The degree of brain loss in patients who received placebo within 12 months was comparable to the extent of brain loss within 18 months of patients who received solanezumab. In other words, the monoclonal antibody delayed the disease for 6 months.
In fact, the experiment was completed in September 2012, when it was concluded that there was no significant difference in overall efficacy compared with injection of solanezumab, regardless of the severity of the symptoms. That is to say, this new monoclonal antibody drug has hardly improved the progress of the disease. Later, the severely ill patients were distinguished from the mild patients and reanalyzed, and the conclusion that solanezumab was effective for mild AD patients was obtained.
From being completely ineffective to partially effective, it seems that people are seeing a glimmer of light. "We really can't conceal the joy of the heart, because such antibody drugs have been tested to be ineffective too many times." The developer Gandhi said excitedly when he heard the news.
The ultimate cause is still questioned
Gandhi said those words because Pfizer and Johnson & Johnson announced on August 6, 2012 that the phase III clinical trial of anti-Aβ monoclonal antibody bapineuzumab has failed. Coincidentally, Eli Lilly and Company also announced on November 23, 2016 that the latest completed large-scale human trial involving 2,000 early AD patients still yielded a disappointing conclusion that solanezumab had no significant effect compared with placebo.
Since then, people began to doubt whether Aβ is really the cause of AD? The neuroscientist George Perry of the University of Texas at San Antonio has publicly questioned the "Aβ hypothesis," and he even believes that Aβ may be the wrong target for the treatment of AD.
There are indications that both Aβ and AD may be the result of illness, not the cause of the disease. It is speculated that the true cause of AD may involve multiple environmental factors such as biotic and abiotic (physical, chemical) aspects. As early as 2010, scientists at the Massachusetts General Hospital found that Aβ is an anti-microbial protein naturally produced by the human body. It acts like an early warning molecule of microbial infections.
In other words, once Aβ is present in the brain, it indicates that there is a certain pathogen infection. At the end of 2016, the research team at the University of California, Davis, said that the bacterial lipopolysaccharide and flagellin components were detected in the Aβ deposits in the brain of AD patients. This suggests that the formation of Aβ in the brain is likely to be caused by bacterial invasion or leakage of bacterial components.
Infection and inflammation might be the cause
The early warning signal from Aβ induces inflammation of immune cells (such as macrophages and microglia), releases nitric oxide and reactive oxygen to kill pathogens, and then Aβ degrades automatically. However, Aβ in the brain of AD patients accumulates to form plaques, which is obviously a problem of Aβ degradation, and all of this is caused by inflammation.
As Dr. Maria Carriro, Chief Scientific Officer of the Alzheimer's Association, said: "Inflammation plays an important role in the development of AD and other neurodegenerative diseases." The association announced in the first half of 2016 that it will invest $1 million to explore the possible link between neuroinflammation and Alzheimer's disease.
For the reason that Aβ cannot be degraded in infected inflammatory brain tissue, the results of the research published by the University of California, San Diego, together with other institutions in early 2016 made a reasonable explanation. The degradation of Aβ is dependent on the synergistic effect of insulin-degrading enzymes and kinesin-related protein-1, but the cysteine-reactive groups in these two proteins are inactivated by nitric oxide (nitrosylation) that is triggered by inflammation, causing Aβ to degrade and deposit. Based on this, it is speculated that the onset of AD is gradual, and its condition deteriorates with the persistence of infection, the increase of inflammation, and the accumulation of Aβ.
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