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  • The amyloid-β protein, which plays a central role in the development of Alzheimer’s disease, occurs in multiple different forms in the brain.
  • Certain subtypes of the amyloid-β protein have links with the development of brain pathologies that health experts observe in Alzheimer’s disease.
  • A new study reports the identification of a novel site on a subtype of the amyloid-β protein, which could allow this amyloid-β protein subtype to be selectively targeted using antibodies or through vaccination.
  • The selective targeting of this amyloid-β protein subtype has the potential to reduce side effects.
  • The monoclonal antibodies and vaccine candidates that researchers developed using this approach effectively reduced symptoms in two mouse models of Alzheimer’s disease.

Alzheimer’s disease (AD) accounts for 60–70% of all dementia cases and is the sixth leading cause of death in adults in the United States.

Doctors characterize the condition by a progressive decline in cognitive abilities, including memory, reasoning, thinking, australian medicines information and language. Although there are a few drugs that can reduce AD symptoms, there is an absence of treatments, except for the controversial drug aducanumab, which can slow the progression of the disease.

Scientists have conducted a large number of clinical trials to find drugs for the treatment of AD, but nearly all of these studies have ended in failure.

Now, a collaboration between researchers from the University of Leicester in the United Kingdom, the University Medical Center Göttingen in Germany, and Life Arc, a U.K. medical charity, has resulted in the development of two novel candidate immunotherapies that could alter the progression of the condition.

According to the amyloid hypothesis, health experts believe the amyloid-beta (amyloid-β or Aβ) protein plays a causal role in AD.

Scientists have characterized multiple different variants of the amyloid-β protein. Evidence suggests that certain variants may be more toxic to brain cells and may play a larger role in the development of AD.

Study co-author, Dr. Mark Carr, a professor at the University of Leicester, told Medical News Today, “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.”

In the present study, the researchers developed two novel treatments that selectively target the specific form of amyloid-β protein.

The monoclonal antibodies, called TAP01, against this protein could help treat patients with AD. In contrast, the vaccine, called TAPAS, would teach the immune system to recognize this protein and help prevent the condition in healthy individuals.

“Both the [monoclonal] antibodies and peptide vaccine targeting the form of amyloid-beta identified to drive AD progression have been shown to dramatically reduce [or] halt disease progression in two mouse models of AD. The very beneficial effects seen on AD progression in mouse models are far greater than seen for any candidate therapeutic antibodies that target amyloid-beta plaques,” said Dr. Carr.

The study appears in the journal Molecular Psychiatry.

Amyloid-β oligomers

AD is characterized by the accumulation of the amyloid-β protein into insoluble aggregates between neurons called amyloid-β plaques.

Single units or monomers of the amyloid-β protein link to form small chains of several units, called oligomers. These soluble oligomers then self-assemble to form fibrils, which eventually cluster to form insoluble plaques.

Experts previously thought the formation of these amyloid-β plaques triggered neurodegenerative processes, resulting in the functional and cognitive impairments characteristic of AD. However, drugs that clear plaques have not been successful in improving the symptoms of the condition in animal models and some clinical trials.

Instead, studies from the past two decades suggest amyloid-β oligomers may be responsible for the neurodegenerative effects of the amyloid-β protein.

Multiple forms of amyloid-β protein are present in the brain and tend to vary in length. The different variants of the amyloid-β protein include the full-length forms, Aβ1-42 and Aβ1-40, and the shorter forms, AβpE3-42 and Aβ4-42.

Although Aβ1-42, one of the therapeutic targets for AD, can form oligomers, these oligomers tend to aggregate rapidly into less toxic plaques.

In contrast, the shorter or truncated variants of the amyloid-β protein tend to form soluble oligomers that persist for longer.

Notably, these truncated amyloid-β protein variants are abundantly present in the brains of individuals with AD. Moreover, the oligomers of these truncated variants have neurotoxic effects and can disrupt the communication between brain cells.

Immunotherapies for AD

Experts have developed antibodies that target amyloid-β protein monomers to prevent toxic oligomers from forming. But there are a few shortcomings to this approach.

These antibodies also bind to the full-length amyloid-β proteins, which play an essential role in normal biological processes in the brain. Therefore, these antibodies are likely to produce side effects.

Moreover, they can also bind to amyloid-β plaques. One of the initial antibodies developed to treat AD showed that the binding of the antibody to amyloid-β plaques had links to side effects in some individuals.

The researchers involved in the present study had previously identified a mouse antibody that selectively binds to the truncated amyloid-β proteins, but not the full-length variants or the amyloid-β plaques.

In the current study, the team produced an engineered or humanized version of this antibody: TAP01_04. Humanized antibodies are designed to bind to the same target as the mouse antibody but are modified to resemble human antibodies.

Humanized antibodies, unlike mouse antibodies, do not produce a strong immune response upon administration, therefore minimizing side effects. Experts could administer the TAP01_04 antibody to people with AD to potentially slow the progression of the disease.

The researchers also wanted to generate a vaccine that would confer protection against AD in healthy individuals.

Vaccines train the body to produce an immune response against a target protein responsible for a disease or as a part of a pathogen. Here, the researchers wanted to prime the immune system to identify and remove the truncated amyloid-β proteins.

However, the researchers could not use the truncated amyloid-β proteins for vaccination directly. This was because these proteins were not stable in solution and had a tendency to aggregate together.

Consequently, the researchers identified the binding site on the truncated amyloid-β proteins that the TAP01_04 antibody detected using a technique called X-ray crystallography.

Although several antibodies can bind to these truncated amyloid proteins, the site that TAP01_04 targeted was unique. This may explain why TAP01_04, unlike other antibodies, binds selectively to truncated amyloid-β proteins but not full-length amyloid proteins or plaques.

The researchers used this information to design a stable form of the amyloid-β protein fragment. This designer protein, called the TAPAS vaccine, shared the binding site for the TAP01_04 antibody with the truncated amyloid proteins.

Study co-author Dr. Thomas Bayer, a professor at University Medical Center Göttingen, noted:

“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,” explained Dr. Bayer.

Effectiveness in mouse models of AD

The researchers then assessed the therapeutic effects of the cyclic designer protein (the TAPAS vaccine) and the TAP01_04 antibodies in two mouse models of AD.

Immunization with either the cyclic designer protein or the humanized TAP01_04 antibody reduced the levels of amyloid plaques in the brains of the AD mouse model. This shows that while both approaches do not target plaques directly, they can reduce the formation of these aggregates by targeting amyloid-β monomers.

The researchers then examined the impact of these immunization approaches on glucose metabolism in the brain, which AD diminishes. Both immunization approaches were able to rescue this reduction in glucose metabolism in a mouse model of AD.

Health experts characterize AD by memory loss and the loss of neurons in specific brain regions, including those involved in memory.

The researchers found that both the TAPAS vaccine and the humanized TAP01_04 antibody effectively improved performance in a memory task in a mouse model of AD. At the same time, both approaches reduced the loss of neurons in the hippocampus, a brain region that plays a central role in the formation of memories.

These results suggest that both the TAPAS vaccine and the TAP01_04 antibody were effective in reducing brain markers associated with the progression of AD.

Clinical trials and intended use

The researchers plan to conduct further animal studies and subsequent clinical trials following the success of the two immunization approaches.

Dr. Carr said, “The humanized TAPAS therapeutic antibodies could be taken into human clinical trials within 3–6 months of finding a suitable pharmaceutical partner. The timeline for human clinical trials of the TAPAS vaccine is less certain and would probably require safety trials in a primate first, but within 2 years of finding a commercial partner with vaccine expertise could be possible.”

“The vaccine needs a few more studies regarding which adjuvant works best in humans. We have used a typical mouse adjuvant. Also, how long the triggered immune response will last is not known at the moment,” added Dr. Bayer.

Dr. Bayer also explained how they intended to utilize the two immunization approaches to treat AD. Dr. Bayer said, “The TAP01_04 antibody is ready to be studied in clinical trials, has less expected side effects, but needs to be supplied to patients on a regular basis, for example, once every month. As such, it will be costly for the health insurance system, like all other antibody drugs.”

“On the other side, it will be helpful for [older] patients, who often have a less effective immune system. TAP01_04 is suited for a therapeutic treatment design after the clinical symptoms have already developed in patients. We believe it will be helpful for acute treatment of Alzheimer’s, not chronic application. This means for a shorter time.”

“The TAPAS vaccine is well suited for a preventative treatment strategy before AD has developed. Importantly, it is produced at much lower costs and therefore much better suited to treat a larger population,” said Dr. Bayer.

Diverging assessment

Medical News Today also spoke to Dr. Jeffrey Fessel, a professor at the University of California, San Francisco. Dr. Fessel, who was not involved with the study, said, “Clearing cerebral amyloid, even completely, is no guarantee that AD would be reversed.”

“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,” added Dr. Fessel.

Besides identifying effective approaches for treating AD, Dr. Fessel stressed the importance of taking preventative measures, such as thiamine supplementation.

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