Antibodies that can remove toxic protein plaques in the brains of mice may lead to treatments that halt the brain damage caused by Alzheimer's disease.

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What role do antibodies (depicted here) have in treating Alzheimer's?

This was the conclusion that researchers came to after investigating antibodies that target the apolipoprotein E (APOE) protein in a mouse model of Alzheimer's disease.

One of the antibodies that they tested halved levels of toxic plaques in the mice's brains.

The researchers also suggest that because the antibodies only target the APOE protein in the plaques, not the plaques themselves, they would likely only cause a small immune reaction.

A large immune response, however, can inflame the brain.

The researchers report their findings in a paper about to be published in the Journal of Clinical Investigation.

Alzheimer's disease destroys brain cells

Alzheimer's disease kills neurons, or brain cells, and gradually erodes our capacity to remember, think, hold a conversation, make decisions, and take care of ourselves.

It is the main type of dementia and the sixth leading cause of death in the United States, where there are 5.7 million people living with the disease.

As the U.S. population ages, the burden of Alzheimer's and other dementias is set to grow from $277 billion to $1.1 trillion between 2018 and 2050.

While changes in brain tissue are known to occur before the behavioral symptoms of Alzheimer's emerge, it is not clear what causes the disease and there is currently no cure or treatment that effectively slows it down.

As the disease progresses, it disrupts metabolism, repair, and communication in and among brain cells, causing them to gradually stop working and die.

Toxic protein plaques

From examining brain tissue from people who had Alzheimer's when they died, researchers have learned a lot about the molecular and biological changes that occur as the disease progresses.

One hallmark of Alzheimer's disease is deposits, or plaques, of protein that build up outside of brain cells and disrupt their function.

The main component of the plaques is fragments of a naturally occurring amyloid precursor protein, one of which — called beta-amyloid 42 — is considered to be particularly toxic to brain cells.

"Many people," explains senior study author David Holtzman, who is a professor and head of the Department of Neurology at Washington University School of Medicine in St. Louis, MO, "build up amyloid over many years, and the brain just can't get rid of it."

Prof. Holtzman and team are keen to find a way to clear the plaques from the brain, preferably before they have a chance to inflict the damage that disrupts brain function.

Targeting the APOE protein

Carrying a variant of the APOE gene is one of the strongest risk factors for developing Alzheimer's disease.

Carrying a variant that raises the risk of a disease is not the same as inheriting the disease. Some people may have the higher-risk variant of the gene and not ever develop the disease.

The APOE gene instructs cells on how to make the APOE protein, which then combines with lipids to make lipoproteins that help to carry cholesterol and other fats in the blood. This is important for preserving the health of blood vessels and preventing cardiovascular diseases.

Carrying the e4 version of APOE, however, increases the risk of developing Alzheimer's disease. While it is not clear how this relates to the cause of disease, scientists have found that it is tied to having more amyloid plaques in the brain. The amyloid plaques also contain small amounts of the APOE protein.

In previous work, Prof. Holtzman and colleagues showed how a DNA-based molecule known as an "antisense oligonucleotide" — which interferes with the production of the APOE protein — halved brain damage in a mouse model of Alzheimer's disease.

However, while lessening the damage caused by the plaques is a significant achievement, an even better one would be to get rid of them altogether. This is why the team set out on the new study.

Targeting the APOE protein with antibodies

When they explored how antibodies might help, the researchers discovered that there is a group of them that attaches to the APOE protein. This is an action that summons patrolling immune cells to dispose of the antibody and the attached protein.

This led them to wonder whether or not summoning immune cells to carry off antibodies bound to the APOE protein in the plaques might also get them to carry away the toxic amyloid protein.

They decided to test the idea in mice that carried a human APOE gene and had been genetically engineered to develop toxic amyloid plaques.

The researchers developed a group of antibodies that can recognize and attach to the human APOE protein.

They put the mice into different groups and gave them weekly injections. Each group received a different antibody, with one group receiving a placebo. This continued for 6 weeks, after which time the researchers examined the mice's brains.

The results demonstrated that plaque levels were halved in the group of mice that received an antibody called HAE-4.

The researchers also found that the antibody only affected the APOE protein in the brain; it did not affect levels in the blood. This was a significant — if somewhat mysterious — result, given the important role that the APOE protein has in the blood transport of fats and cholesterol.

Potential for reduced side effects

When they investigated further, the researchers found that the structure of the APOE protein in brain plaques is different to that of the APOE protein in the blood.

"The HAE-4 antibody recognized only the form found attached to the plaques in the brain," Prof. Holtzman explains.

Trials of antibodies that might clear plaques are already under way. However, the researchers point out that many of these are antibodies that bind to most of the molecules in the toxic deposits. Therefore, they may trigger a sizeable immune reaction that inflames the brain.

Prof. Holtzman says that their hope is that, by using antibodies that only bind to the APOE protein in the brain, they might still succeed in removing plaques, but, because of "less immune activation [...] we might not see the unwelcome side effects."

He and his colleagues are now embarking on further research to discover antibodies that have the same effect as they saw in the mice and are safe to use in humans.

"By removing plaques, if we start early enough, we may be able to stop the changes to the brain that result in forgetfulness, confusion, and cognitive decline."

Prof. David Holtzman

Some of the authors have declared interests in a patent filed jointly with Denali Therapeutics, who helped to develop the antibodies and part-funded the study. Prof. Holtzman also consults for the company, as he does for several other biotechnology companies.