Subscribe to eTOC

Targeting Two Amyloid Plaque Inhibitors Found Effective and Safe in Alzheimer Disease Mice

ARTICLE IN BRIEF

Investigators reported that genetic reductions of both BACE1 and gamma secretase attenuated the amyloid burden and ameliorated cognitive deficits in transgenic AD mice — with no evidence of toxicity.

Much of Alzheimer disease (AD) research has focused on the development of the therapeutic strategies that target the pathways involved in formation and accumulation of amyloid plaque — a major pathological hallmark of the disease.

One attractive therapeutic target is amyloid beta (Abeta), which accumulates in plaques in the hippocampus and the cerebral cortex of patients with AD. The hope is to reduce the build-up of a toxic cleavage product of amyloid precursor protein (APP) by interfering with its processing by two important enzymes — gamma secretase and beta-site APP cleaving enzyme (BACE1).

But it is becoming clear that complete inhibition of gamma secretase or BACE1 is not the way to go, Vivian W. Chow, PhD, a fellow in the Division of Neuropathology at John Hopkins School of Medicine, told Neurology Today. Prior studies in animal models of disease have shown that completely knocking out BACE1 or gamma secretase could lead to potentially adverse side effects, she explained, including impairment in synaptic functions, hypomyelination of axons of sciatic and optic nerves, schizophrenia-like endophenotypes, and skin tumors. Earlier studies conducted by Tong Li, PhD, and colleagues at Johns Hopkins, for example, found that mice that had reduced gamma secretase activity by 50 percent or more developed skin tumors, head and neck cancers, as well as enlarged spleens and livers.

And so Dr. Chow and colleagues decided to try something new — to test the benefits of a combination therapy to target the two enzymes needed to cut Abeta from APP. The rationale behind this strategy was based on previous studies showing that moderate reduction of either BACE1 or gamma secretase provided modest anti-amyloid benefit without causing problems associated with complete knockout of BACE1 or gamma secretase. They then tested whether modest reduction of both enzymes simultaneously would provide even greater protection.

STUDY PROTOCOLS, RESULTS

In a paper in the Jan. 6 online journal Science Translational Medicine, the investigators reported that genetic reductions of both BACE1 and gamma secretase attenuated the amyloid burden and ameliorated cognitive deficits in transgenic AD mice — with no evidence of toxicity.

To conduct their experiments, the investigators first developed mice that carry only one gene (allele) for BACE1 and Aph-1a, an essential component of gamma secretase. Normal mice carry two copies of these genes in every cell. This strategy knocked out BACE1 and gamma secretase by 50 and 30 percent, respectively. These mice were crossed with an AD mouse model that expresses two mutant genes, APP and presenilin 1(PS1), which cause familial AD.

The good news was that the reduction of gamma secretase and BACE1 showed a reduced burden of amyloid plaques in AD models. The amyloid burden was significantly reduced — by 70 percent in the hippocampus and 50 percent in the cerebral cortex — at a time corresponding to the late stage of AD.

The investigators also used an antibody to tag Abeta oligomers, which, when accumulated, is linked to neuronal dysfunction, impaired synaptic plasticity and memory in animal models; and their transgenic mouse model showed a significant decrease of these Abeta oligomers.

The investigators tested cognition by putting the aging mice in a water maze to see if their memory was protected. The animals with modest reductions of both enzymes did much better at finding the underwater platform than animals with the standard AD mutations. Importantly, modest reduction of beta secretase and gamma secretase did not result in any side effects observed in the mice with significant reductions in secretase activities.

In fact, said Dr. Chow, the animals are now almost three years old and they look as normal as wild type control mice. So far, the effects have only been studied in these animals.

Figure

DR. DAVID A. DRACHMAN: “Unless reduction of Abeta can be shown to be clinically useful in human AD, the value of strategies to reduce toxicity remains moot. So, we await proof-of-principle that reducing Abeta will prevent or improve human AD.”

NEXT STEP FOR RESEARCH

The next step is to test whether this idea could be designed with patients in mind. The clinical challenge is to identify compounds or drugs that will show promise for inhibiting either BACE1 or gamma secretase. Once that is accomplished, Dr. Chow said, then a combination therapeutic approach can be considered.

She said that scientists need to look for toxicity associated with the drugs that inhibit either BACE1 or gamma secretase. It isn't clear how much scientists will need to inhibit this enzyme combination to avoid side effects. In assessing the dosage required, one will need to empirically determine what dosage of inhibition of BACE1 and gamma-secretase would be appropriate for humans, which may be different than that of mouse models, Dr. Chow said. This will need to be established for each target separately and then in combination in clinical testing.

And ultimately the usual concerns about comparing mouse to man looms large. “There is always a big concern and experience tells us that findings from transgenic mouse models may not always be applicable in the human setting,” said Dr. Chow. “The same is true for calibrating the appropriate dose that would provide efficacy while limiting adverse affects of the drug,” she said. “Results from our translational research provide the proof-of-concept and validate this anti-amyloid combination therapeutic strategy for prevention and treatment of Alzheimer disease, one which now can be tested in the clinic to prove its validity for humans.”

EXPERT COMMENTARY

AD experts agree that the finding is intriguing but will require a lot more work. This study by the Hopkins group is a meticulous tour de force, the thrust of which is that partial reductions of both BACE1 and gamma secretase in the so-called “AD mouse model” can cause minimal toxicity, while reducing brain Abeta, said David A. Drachman, MD, professor of neurology and chairman emeritus at the University of Massachusetts Medical School. “The key question, though, is whether even a safe means of reducing Abeta would be useful in the treatment or prevention of human AD.”

The AD transgenic mouse model is remote from most human AD, Dr. Drachman pointed out. Loaded with both presenilin and APP mutations to produce a large excess of Abeta, it differs from even the rare 3 percent of human AD, where either a presenilin or an APP mutation — and never both — is present; and is unlike the other 97 percent of human AD patients who have neither mutation.

Whatever the underlying cause, however, many Abeta-reducing treatments have been shown to work in mouse AD, but to date, none shown significant clinical benefit in human trials, Dr. Drachman said. “Unless reduction of Abeta can be shown to be clinically useful in human AD, the value of strategies to reduce toxicity remains moot. So, we await proof-of-principle that reducing Abeta will prevent or improve human AD. Decreasing toxicity of Abeta treatments in the AD mouse model is an interesting observation whose potential clinical value remains unclear.”

References

Chow VW, Savonenko AV, Wong PC, et al. Modeling an anti-amyloid combination therapy for Alzheimer's disease. Sci Transl Med 2010; 2(13): 13ra1.