- The amyloid protein, which plays a key role in the progression of Alzheimer’s disease, can be found in a variety of forms in the brain.
- Certain subtypes of the amyloid protein have been linked to the development of brain diseases seen in Alzheimer’s disease, according to specialists.
- A new study reveals the discovery of a novel location on a subtype of amyloid protein that could allow antibodies or vaccination to preferentially target this subtype of amyloid protein.
- The ability to target this amyloid-protein subtype selectively may lessen negative effects.
- Researchers used this strategy to develop monoclonal antibodies and vaccine candidates that significantly reduced symptoms in two mouse models of Alzheimer’s disease.
Alzheimer’s disease (AD) is the sixth greatest cause of death in adults in the United States, accounting for 60–70% of all dementia cases.
The disorder is defined by a steady deterioration in cognitive functions such as memory, reasoning, thinking, and language, according to doctors. Except for the controversial medicine aducanumab, which can halt the advancement of the disease, there are no treatments for Alzheimer’s disease, despite the fact that a few drugs can alleviate symptoms.
Scientists have done a significant number of clinical trials in order to develop medications to cure Alzheimer’s disease, but nearly all of them have failed.
Researchers from the University of Leicester in the United Kingdom, the University Medical Center Göttingen in Germany, and Life Arc, a UK medical charity, have now developed two novel candidate immunotherapies that could slow or stop the progression of the disease.
According to the amyloid hypothesis, the amyloid-beta (amyloid- or A) protein has a causative role in Alzheimer’s disease.
Multiple variations of the amyloid protein have been identified by scientists. Certain variations may be more hazardous to brain cells and may play a larger role in the development of Alzheimer’s disease, according to evidence.
“We have identified the form of the amyloid-beta protein responsible for driving AD and have shown that specifically targeting this form of the protein in two mouse models of AD results in substantial improvements in key markers of disease progression,” study co-author Dr. Mark Carr, a professor at the University of Leicester, told Medical News Today.
The researchers created two innovative medicines that target a specific kind of amyloid protein in the current investigation.
TAP01 monoclonal antibodies against this protein could aid in the treatment of Alzheimer’s sufferers. The TAPAS vaccination, on the other hand, would teach the immune system to recognize this protein and help healthy people from developing the disease.
“Both [monoclonal] antibodies and peptide vaccines targeting the type of amyloid-beta found to drive AD progression have been shown in two mouse models of AD to dramatically reduce [or] prevent disease progression.” “The highly favorable benefits shown in mouse models on AD development are significantly greater than any prospective therapeutic antibodies that target amyloid-beta plaques,” Dr. Carr explained.
The findings have been published in the journal Molecular Psychiatry.
Amyloid-β oligomers
The accumulation of the amyloid protein into insoluble aggregates between neurons, known as amyloid plaques, is a characteristic of Alzheimer’s disease.
The amyloid protein’s single units, or monomers, bind together to form oligomers, which are tiny chains of multiple units. These soluble oligomers self-assemble into fibrils, which cluster to form insoluble plaques.
Previously, experts believed that the creation of these amyloid plaques started neurodegenerative processes, resulting in the functional and cognitive impairments associated with Alzheimer’s disease. Drugs that eliminate plaques, on the other hand, have failed to improve the symptoms of the disease in animal models and certain clinical trials.
Instead, studies over the last two decades reveal that amyloid-oligomers are responsible for the amyloid-neurotoxic protein’s effects.
In the brain, there are several types of amyloid protein that vary in length. The full-length forms, A1-42 and A1-40, and the shorter forms, ApE3-42 and A4-42, are the distinct variations of the amyloid protein.
Although A1-42, one of the therapeutic targets for Alzheimer’s disease, can form oligomers, these oligomers assemble quickly to create less toxic plaques.
Shorter or truncated amyloid-protein variations, on the other hand, tend to produce soluble oligomers that last longer.
These truncated amyloid-protein variations are particularly common in the brains of Alzheimer’s patients. Furthermore, the oligomers of these truncated variants are neurotoxic and can disrupt brain cell communication.
Immunotherapies for AD
Antibodies that target amyloid-protein monomers have been created to prevent harmful oligomers from developing, according to experts. However, there are a few flaws in this strategy.
These antibodies also attach to full-length amyloid proteins, which play an important part in normal brain biological processes. As a result, these antibodies are likely to cause negative side effects.
Furthermore, they have the ability to attach to amyloid plaques. One of the first antibodies created to treat Alzheimer’s disease revealed that the antibody’s binding to amyloid plaques was linked to negative effects in some people.
The researchers had previously discovered a mouse antibody that selectively attaches to shortened amyloid proteins but not full-length versions or amyloid plaques, according to the findings.
In the current investigation, the researchers created TAP01 04, an engineered or humanized form of this antibody. Humanized antibodies attach to the same target as mice antibodies but are altered to look like human antibodies.
Humanized antibodies, unlike mice antibodies, do not elicit a robust immune response when given, resulting in less adverse effects. Experts may be able to use the TAP01 04 antibody to help people with Alzheimer’s disease slow down their illness progression.
The researchers also aimed to develop a vaccination that would prevent healthy people from Alzheimer’s disease.
Vaccines teach the body to create an immune response to a disease-causing or pathogen-causing target protein. The goal of this study was to train the immune system to recognize and eliminate shortened amyloid proteins.
The researchers, however, were unable to employ the shortened amyloid proteins for direct vaccination. This was due to the fact that these proteins were not stable in solution and tended to agglomerate.
As a result, the researchers used X-ray crystallography to identify the binding location on the truncated amyloid-proteins that the TAP01 04 antibody recognized.
Although many antibodies can attach to these shortened amyloid proteins, TAP01 04 targeted a specific location. This could explain why TAP01 04 binds to truncated amyloid proteins but not full-length amyloid proteins or plaques, unlike other antibodies.
This information was used to create a stable version of the amyloid-protein fragment. The TAPAS vaccine, a designed protein, shared the TAP01 04 antibody’s binding site with shortened amyloid proteins.
Dr. Thomas Bayer, a professor at University Medical Center Göttingen and a study co-author, said:
“For both drugs, we expect fewer side effects as compared to antibody treatments currently tested in clinical trials or even [the one which has been] approved. Both our vaccine and antibody do not react with Alzheimer’s plaques, which is a great advantage. All other competitor antibodies react with plaques and dissolve the toxic amyloid material after binding, thereby causing side effects.”
“Our drugs detect the soluble precursor amyloid peptide before they aggregate in plaques. In the paper, we describe the discovery of a unique and novel crystal structure, the TAPAS epitope, which is only detected by the vaccine antibody and the TAP01_04 antibody and not by any other comparator antibody. For drug developers, this is important to better understand the binding properties,Dr. Bayer added.
Effectiveness in mouse models of AD
In two animal models of Alzheimer’s disease, the researchers tested the therapeutic effects of the cyclic designer protein (the TAPAS vaccination) and the TAP01 04 antibodies.
The AD mouse model’s brains had lower levels of amyloid plaques after being immunized with either the cyclic designer protein or the humanized TAP01 04 antibody. This demonstrates that, while neither strategy directly targets plaques, both can limit the production of these aggregates by focusing on amyloid monomers.
The researchers then looked at how these immunization techniques affected glucose metabolism in the brain, which is affected by Alzheimer’s disease. In a mouse model of Alzheimer’s disease, both immunization techniques were able to reverse the decline in glucose metabolism.
Memory loss and the death of neurons in certain brain regions, including those involved in memory, are the hallmarks of Alzheimer’s disease, according to specialists.
In a mouse model of Alzheimer’s disease, the researchers discovered that both the TAPAS vaccination and the humanized TAP01 04 antibody enhanced performance in a memory task. Both techniques, at the same time, reduced the loss of neurons in the hippocampus, a brain region that is critical for memory formation.
These findings imply that the TAPAS vaccine and the TAP01 04 antibody were both effective in lowering brain markers linked to Alzheimer’s disease progression.
Clinical trials and their intended applications
Following the success of the two immunization techniques, the researchers plan to undertake more animal investigations and clinical trials.
“Within 3–6 months of finding a good pharmaceutical partner, the humanized TAPAS therapeutic antibodies might be taken into human clinical trials,” Dr. Carr added. Human clinical trials of the TAPAS vaccine are less clear, and would almost certainly require primate safety testing first, but could be doable within two years of finding a commercial partner with vaccine experience.”
“A few more research on which adjuvant works best in humans are needed for the vaccination.” We used a standard mouse adjuvant. “At the time, we don’t know how long the triggered immunological response will last,” Dr. Bayer added.
Dr. Bayer also discussed how the two vaccine techniques will be used to treat Alzheimer’s disease. “The TAP01 04 antibody is ready for clinical trials, has less expected adverse effects, but must be given to patients on a regular basis, such as once a month,” Dr. Bayer added. As a result, like all other antibody medicines, it will be pricey to the health-care system.”
“On the other hand, it will be beneficial to [older] individuals, who frequently have a weak immune system.” TAP01 04 is best used as part of a therapeutic treatment plan once patients have acquired clinical symptoms. We feel it will be beneficial for acute Alzheimer’s treatment rather than long-term use. This translates to “for a shorter period of time.”
“The TAPAS vaccine is ideally suited for use as a preventative treatment method before the onset of Alzheimer’s disease.” Importantly, it is generated at a reduced cost, making it better suited to treating a bigger population,” Dr. Bayer explained.
Divergent opinions
Dr. Jeffrey Fessel, a professor at the University of California, San Francisco, was also interviewed by Medical News Today. “Clearing cerebral amyloid, even completely, is no guarantee that AD would be reversed. ” noted Dr. Fessel, who was not involved in the study.
“That is for several reasons, chief among which is that AD is multicausal and amyloid is only one of the causes, which implies that the anti-amyloid compound needs support from several other drugs.”
“Another major reason is that the brains of mice differ in several highly important ways from the human brain, e.g., astrocytes comprise 50% of human brain cells, but only 20% of mice brain cells. Those are the two main reasons why pharma has fruitlessly spent billions of dollars, but no anti-amyloid compound has done more than induce minor benefit in AD patients.”
“Unfortunately, the amyloid hypothesis still captivates researchers, most of whom seem to have a narrow-angle field of vision. Another pyroglutamate-modified anti-amyloid-β is welcome but is not game-changing because we already have donanemab, which, given alone, provides minor benefit, but if it were administered with helper drugs, might have a chance at reversing AD, according to Dr. Fessel.
Dr. Fessel emphasized the significance of pursuing prophylactic measures, such as thiamine supplementation, in addition to developing effective techniques for treating AD.
