An ounce of prevention:
Todd Golde uses monoclonal antibody therapy to prevent amyloid deposition in a mouse model

According to Todd Golde, MD, PhD, Mayo Clinic College of Medicine, enough is known about the mechanisms of Alzheimer’s disease (AD) to know this: Preventing the devastating neurodegenerative disease is likely to be far easier than finding a cure for it. In a recent study in which monoclonal antibodies were given to mice predisposed to AD, Golde, who is a recipient of the Paul B. Beeson Award, took a great leap forward in understanding just how it might be done.

Golde’s study was based on a body of genetic, pathologic, and biophysical data indicating that a type of protein fragment, known as Aß₄₂ (pronounced “a-beta-42”), is the molecular trigger that initiates AD. The Aß₄₂ fragment is just one of a score that are produced when a larger protein—amyloid precursor protein, or APP—is cut into pieces.

“Although there are a plethora of beta-amyloid species produced,” Golde says, “the two we talk about most are Aß₄₀, which is 40 amino acids long, and Aß₄₂, which is 42 amino acids long. Although the body makes more of Aß₄₀ normally, it’s the Aß₄₂ form that seems to deposit earliest and most predominantly in the AD brain.”

What makes Aß₄₂ so nefarious is its “stickiness.” It is described as being highly amyloidogenic, which means it is more likely to form fibrils in physiological conditions than other shorter Aß species, including Aß₄₀. In a person with AD, these fibrils will join with other fibrils to form mats known as beta-sheets. The beta-sheets, in turn, are the primary component of plaques—the defining characteristic of the AD brain.

Because Aß₄₂ is so closely associated with the development of AD, Golde wanted to test whether selective reduction of Aß₄₂ might be an effective way to treat or prevent the disease. One approach would have been to raise an active immunization response against Aß₄₂. In active immunization, a small amount of a foreign protein is injected into the body, which produces antibodies that recognize and destroy the foreign protein on any subsequent appearance. This is the principle behind most vaccinations, and in 2005, clinical trials designed to test an AD vaccine (AN-1792) were halted when some of the vaccine recipients developed brain inflammation.

On top of that, the vaccine didn’t produce a robust immune response. “One of the things your immune system is supposed to be good at is recognizing self from non-self,” Golde explains. “So there are some inherent checkpoints that prevent the immune system from raising an immune response against a self-antigen. Because you normally make Aß, when you’re immunized with it, you have a blunted immune response.”

To overcome these challenges, Golde used a passive immunization approach based on monoclonal antibody technology. Monoclonal antibodies are laboratory-produced antibodies made by injecting a mouse with an antigen, letting the mouse develop antibodies, and then collecting the antibodies for use in a human system. Because the antibodies come from a mouse, they are recognized as foreign by the human immune system.  

“You can’t give a mouse antibody to a human,” Golde says, “because you get an antibody response against the mouse protein. It will be neutralized after one or two rounds of treatment.”

For human therapy, then, monoclonal antibodies gathered from mice have to be “humanized,” just one step of a complex and expensive process. Fortunately for Golde, he wasn’t trying to develop a human therapy. His was a proof-of-concept study, or a study trying to test what would happen if Aß₄₂ was selectively reduced in an animal model. Because both the source of the monoclonal antibodies and the subjects of the study were mice, Golde didn’t have to worry about any self/non-self issues.

To study the effects of anti-Aß₄₂ monoclonal antibodies, Golde set up two experiments. In the first, he administered the anti-Aß₄₂ monoclonal antibodies prior to any significant amyloid deposition in the mice. “In human terms,” Golde observes, “this would be like receiving antibodies 10 years before any clinical symptoms of Alzheimer’s disease appear.” The results of this experiment showed that these mice, immunized with anti-Aß₄₂ monoclonal antibodies over time, had a significant reduction in subsequent amyloid deposition.

However, as the second experiment demonstrated, waiting until the animals had higher levels of amyloid before they received antibodies produced very different results. According to Golde, “The efficacy of the anti-Aß₄₂ monoclonal antibodies is a lot worse when you start late. In other words, a human showing early signs of AD, such as mild cognitive impairment, would likely receive less benefit from receiving anti-Aß₄₂ monoclonal antibodies. That suggests it’s easier to prevent deposition than do anything about it once it’s started.”

Golde says there are analogies among other diseases. “If you have a plaque filling your artery and you’re having chest pains from that, you need a bypass, not just a cholesterol-lowering medication such as a statin. A statin might help to prevent a second blockage after a bypass or other surgical intervention, but it isn’t going to get rid of the preexisting cholesterol plaque all by itself.”

For people who have Alzheimer’s disease right now, this might seem discouraging. But as Golde points out, some promising drugs are currently being developed. Flurizan, now in Phase II clinical trials for the treatment of mild to moderate Alzheimer’s disease, is one of these drugs.

In the future, prevention of Alzheimer’s disease—not treatment—may well be the focus of the medical community. “I will place a bet with a high degree of confidence,” Golde says, “that we will have preventive therapy for AD long before we have stem cell therapy or another type of therapy that truly and completely reverses clinical dementia. The tools are there, we understand the disease process well enough, and the key to prevention is developing safe therapies. Monoclonal antibody approaches, although expensive, are likely to be safe and effective.”