The Tangled Path of Alzheimer's Disease

β-amyloid: invisible enemy or secret protector?

Oksana Goryainova, Olga Posukh, "Biomolecule"

Alzheimer's disease is a neurodegenerative disease with extremely depressing symptoms: patients become helpless, lose touch with reality and even lose the ability to speak. In particular, clinical trials of two drugs aimed at destroying β-amyloid particles – structures associated with the development of Alzheimer's disease - were conducted at once. At the same time, experiments on living organisms have confirmed the assumption that beta-amyloid has beneficial properties for our body – it is an important element of innate immunity.

Alzheimer's disease usually develops in people over the age of 65. Externally, it is manifested by the triad "apraxia-agnosia-aphasia": a person loses the ability to perform elementary actions, recognize objects and people's faces, his speech activity is disrupted. In this case, deviations in the behavior of patients are preceded by physiological changes in their body. 10-15 years before the first manifestations of the disease, so-called beta-amyloid plaques begin to be deposited in the brain. These characteristic clusters are formed mainly by β-amyloid, a peptide formed by a special enzymatic cleavage of the β-amyloid precursor protein. Many researchers believe that these formations contribute to the progressive degeneration of brain cells, and therefore they are developing drugs aimed at destroying or reducing the number of β-amyloid clusters. In 2016, two such anti-amyloid drugs were undergoing clinical trials at once.

One of these drugs was developed in Switzerland. Initially, scientists took blood samples from elderly people who did not show any cognitive impairment. Then they isolated B-lymphocytes from the selected blood. At the same time, it was important to isolate such cells whose antibodies would recognize "toxic" β-amyloid plaques, but not the precursor protein. The fact is that the precursor of beta-amyloid is present throughout the body and plays an important role in the growth of nerve cells, therefore it is extremely undesirable to affect it – it can harm health. As a result, the monoclonal antibody aducanumab was obtained [1]. It selectively reacts with harmful β-amyloid, but does not attack the useful precursor protein. Presumably, this antibody can help patients at an early stage of Alzheimer's disease.

To date, the first phase of clinical trials of aducanumab has already been completed [2], [3]. 165 patients at an early stage of Alzheimer's disease were treated with this antibody: some of them received aducanumab, and some (control group) – placebo. Comparing such groups with each other, it is possible to judge the effectiveness of the drug. It turned out that in patients from the placebo group, cognitive abilities significantly decreased, whereas in patients receiving the antibody, they stabilized. This was checked using standard questionnaires to assess cognitive abilities. Also, using positron emission tomography (PET), scientists found that aducanumab helps to reduce beta-amyloid deposits in the brain. New clinical trials are currently being conducted to further evaluate the safety and efficacy of aducanumab.

The second drug was obtained by researchers from the USA and Canada [4]. It is called verubecestat, and its function is to inhibit the enzyme beta-secretase (BACE1). This enzyme is one of the main "producers" of β-amyloid in the brain. Studies conducted on rodents and primates have shown that in animals taking verubecestat for 6-9 months, the content of beta-amyloid in the central nervous system decreased markedly. Unfortunately, the results were not so inspiring when it came to treating people.

In February 2017, it was decided to discontinue clinical trials of verubecestat, since the drug did not show effectiveness in combating already developed Alzheimer's disease – at least in the case of early or moderate dementia. Independent experts agreed that in this case there is practically no chance of getting a positive clinical effect. However, researchers do not lose hope: there is a possibility that verubecestat is suitable for the treatment of patients with the first manifestations of Alzheimer's disease. The results of these clinical trials will be announced in February 2019.

Recently, the amyloid hypothesis of the development of Alzheimer's disease is gradually losing its position. One of the main facts refuting the stable opinion about the harmfulness of β-amyloid, researchers from Massachusetts General Hospital [5], [6]. It turned out that β-amyloid is a normal component of innate immunity. Previously, scientists confirmed this assumption in in vitro experiments, that is, they demonstrated the corresponding effects in model systems outside of a living organism [7]. Now they have obtained similar results in experiments in vivo, that is, on living organisms. New studies on mice and roundworms, as well as experiments with cultured human brain cells, have shown that beta-amyloid is able to protect the body from potentially lethal infections.

Scientists compared synthetic forms of beta-amyloid with cathelicidin, an antimicrobial peptide that helps to cope with invasive bacterial infections. It turned out that β-amyloid inhibits the growth of several dangerous pathogens in the same way, and sometimes even better, than cathelicidin. β-Amyloid isolated from the brains of patients with Alzheimer's disease suppressed the growth of cultured Candida yeast, and its synthetic analogue was effective against influenza and herpes viruses. Scientists also found that transgenic mice that expressed the human β-amyloid gene lived much longer after salmonella infection than their normal relatives. And mice devoid of any amyloid precursor died the fastest. Transgenic expression of β-amyloid protected roundworms and neuron cultures from infection with Candida and Salmonella microorganisms. And, like the cherry on the cake, the last fact: human beta-amyloid synthesized by living cells turned out to be 1000 times more effective in fighting infections compared to its synthetic analogues.

Why is this happening? Probably, the antimicrobial effect of β-amyloid is explained precisely by its ability to form aggregates: its molecules bind to the surface of microbes, and then combine into dense structures, which prevents the attachment of pathogenic microorganisms to the cells of the macroorganism. Then why do amyloid plaques accumulate in the brain? Scientists do not rule out the following option: perhaps, for some reason, the brain begins to perceive itself as "attacked" by invading pathogens (and, perhaps, in reality, it is), as a result of which enhanced amyloid production is triggered. But further research is needed to confirm this hypothesis.

So what is the outcome? How to treat Alzheimer's disease? Unfortunately, there is no obvious answer to this question yet. However, given the new data, it should be understood that the total destruction of beta-amyloid can be fraught with negative health consequences. The amyloid hypothesis looks less promising, and scientists will have to look for new targets for the treatment of this serious ailment. I want to believe that the era of new drugs against Alzheimer's disease is just around the corner.

Literature

1. Biomolecule: Monoclonal antibodies;

2. Jeff Sevigny, Ping Chiao, Thierry Bussière, Paul H. Weinreb, Leslie Williams, et. al.. (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 537, 50-56;

3. Antibody reduces harmful brain amyloid plaques in Alzheimer’s patients. (2016). Science Daily;

4. M. E. Kennedy, A. W. Stamford, X. Chen, K. Cox, J. N. Cumming, et. al.. (2016). The BACE1 inhibitor verubecestat (MK-8931) reduces CNS  -amyloid in animal models and in Alzheimers disease patients. Science Translational Medicine. 8, 363ra150-363ra150;

5. D. K. V. Kumar, S. H. Choi, K. J. Washicosky, W. A. Eimer, S. Tucker, et. al.. (2016). Amyloid-  peptide protects against microbial infection in mouse and worm models of Alzheimers disease. Science Translational Medicine. 8, 340ra72-340ra72;

6. Human amyloid-beta acts as natural antibiotic in the brain: Alzheimer’s-associated amyloid plaques may trap microbes. (2016). Science Daily;

7. Biomolecule: Perhaps the beta-amyloid of Alzheimer's disease is part of innate immunity.

Portal "Eternal youth" http://vechnayamolodost.ru  14.04.2017