Alzheimer’s drug discovery: looking under the right ROCK

Developing drugs that can change the progression of Alzheimer’s disease is a huge challenge. In the last few years, more than one pharmaceutical firm have abandoned clinical programs in Alzheimer’s that once looked promising. Still, Emory and Scripps scientists have found an approach that deserves a second look and more investigation.

One straightforward drug strategy against Alzheimer’s is to turn down the brain’s production of beta-amyloid, the key component of the disease’s characteristic plaques. A toxic fragment of a protein found in healthy brains, beta-amyloid accumulates in the brains of people affected by the disease.

The enzyme that determines how much beta-amyloid brain cells generate is called BACE (beta-secretase or beta-site APP cleaving enzyme). Yet finding drugs that inhibit that elusive enzyme has been far from straightforward.

Now researchers  have identified a way to shut down production of beta-amyloid by diverting BACE to a different part of the cell and inhibiting its activity. The results were published this week in Journal of Neuroscience.

“This is an indirect but highly effective way of blocking BACE, which controls the chokepoint step in beta-amyloid production,” says lead author Jeremy Herskowitz, PhD, instructor in neurology at Emory’s Alzheimer’s Disease Research Center.

“Jeremy has found a promising approach toward reducing beta-amyloid production and potentially modifying Alzheimer’s disease progression, something for which there is immense need,” says senior author James Lah, MD, PhD, associate professor of neurology at Emory University School of Medicine and director of the Cognitive Neurology program. “Drugs that reduce beta-amyloid production would probably be mostly Ray Ban outlet preventive. However, since amyloid-beta is toxic, they could have some immediate effect on cognitive impairment.”

In the paper, Herskowitz and his colleagues demonstrate that a specific inhibitor of the enzyme ROCK2 can cut beta-amyloid production in brain cells by more than 75 percent. Co-author Yangbo Feng. PhD, Associate Director of Medicinal Chemistry at Scripps Research Institute in Florida, previously discovered the ROCK2 inhibitor, called SR3677.

Alzheimer’s researchers were already interested in ROCK2 and a related enzyme, ROCK1, because of a connection with NSAIDs (non-steroid anti-inflammatory drugs) such as ibuprofen. Some NSAIDS can inhibit production of a particularly toxic form of beta-amyloid, and scientists believed NSAIDs were exerting their effects through the ROCKs.

Herskowitz first showed that in cultured cells, “knocking down” the ROCK2 gene reduced beta-amyloid production, but knocking down ROCK1 had the opposite effect.

“This says that anytime you’re hitting both ROCKs at once, the effects cancel each other out,” he says.

BACE to lysosomes

Red = BACE, Green = lysosomes, Yellow and orange = drug makes BACE go to lysosomes

The known drugs that affect the ROCKs seemed to be doing just that. In contrast, SR3677 inhibits ROCK2 much more effectively than ROCK1, and it offered a way around the obstacle. Herskowitz found that by inhibiting ROCK2, SR3677 diverts BACE to a different part of the cell (lysosomes), where it is less likely to act on beta-amyloid’s parent protein.

He and ADRC colleagues found that ROCK2 levels are higher than usual in tissue samples from brains of patients with Alzheimer’s, including those with mild cognitive impairment, thought to be a precursor stage of the disease.

“There is plenty of ROCK2 in the brain, and its levels are elevated in Alzheimer’s patients, indicating that it’s an excellent drug target,” Herskowitz says. “We are eager to pursue more extensive studies of this strategy in animal models of Alzheimer’s.”

SR3677 can substantially inhibit beta-amyloid production in an animal model of Alzheimer’s, but so far, this effect has been observed when the drug is injected directly into the brain. More studies are required to learn if SR3677 or related drugs can pass the blood-brain barrier and thus be given by injection or orally, and what side effects could appear. ROCK inhibitors are also being investigated for treating other conditions such as glaucoma, hypertension and multiple sclerosis.

*Note: the Gourley lab at Yerkes has been studying the behavior-influencing effects of ROCK inhibitors (not selective to ROCK1 vs ROCK2).

Herskowitz originally was led to examine ROCK2 because in the brain, it interacts with the protein LR11, which Lah’s laboratory previously has established as an important player in Alzheimer’s. Variants in the gene that encodes LR11 have been linked to Alzheimer’s disease risk, and LR11 levels are reduced in the brains of Alzheimer’s patients. In contrast to LR11, ROCK2 levels go up in Alzheimer’s.

We also should mention that although BACE inhibitors are entering clinical trials in 2013 (“after more than a decade of seemingly pushing against a wall,” according to Alzforum), side effects are still a concern. Herskowitz hypothesizes that since animal studies suggest ROCK2 is required in embryonic development but less critical later in life, ROCK2 inhibitors may have an acceptable side effect profile.

Posted on by Quinn Eastman in Neuro Leave a comment

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Quinn Eastman

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