Gradually eliminating BACE1 clears amyloid plaque from mice with Alzheimer’s

Mice specially bred to lose the BACE1 enzyme as they aged were able to clear the amyloid plaques that are characteristic of Alzheimer's. (Alexandra/München)

Researchers from the Cleveland Clinic have reversed the development of amyloid plaque in mice with Alzheimer’s disease by gradually depleting their levels of BACE1. The study buoys hope that targeting this enzyme could become a viable treatment for Alzheimer's.

As BACE1 plays a role in beta-amyloid production, several companies are trying to develop drugs that block the enzyme. But it hasn’t been smooth sailing for them. Most recently, Merck halted a phase 3 trial of its BACE1 inhibitor verubecestat in prodromal, or very early, Alzheimer’s, just a year after calling it quits on a trial in patients with more advanced disease.

The Cleveland Clinic team wanted to block BACE1 in mice, but couldn’t do it too early, because the complete absence of the enzyme leads to developmental brain defects. So they engineered mice that would begin to lose BACE1 as they aged. They then bred these mice with mice that would eventually develop amyloid plaques.

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While the offspring did form plaques, they began to disappear as the mice grew older and gradually cleared BACE1. In addition to lowering the mice’s beta-amyloid levels, the BACE1 depletion also boosted their learning and memory, as measured in a contextual fear conditioning test.

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"Our study provides genetic evidence that preformed amyloid deposition can be completely reversed after sequential and increased deletion of BACE1 in the adult," said Riqiang Yan, of the Cleveland Clinic’s Lerner Research Institute, in a statement. "Our data show that BACE1 inhibitors have the potential to treat Alzheimer's disease patients without unwanted toxicity.”

But the benefits may come with side effects, as BACE1 is involved in other protein processes beyond the production of amyloid-beta.

“Future studies should develop strategies to minimize the synaptic impairments arising from significant inhibition of BACE1 to achieve maximal and optimal benefits for Alzheimer's patients,” Yan said.

Hope for BACE springs eternal, despite repeated failure in Big Pharma programs targeting beta-amyloid. Novartis and Amgen expanded their partnership with Banner Alzheimer’s Institute in November, launching a new trial exploring whether the BACE inhibitor CNP520 can delay or prevent the onset of Alzheimer’s.

And new targets are emerging for treating Alzheimer's. Denali Therapeutics pulled off a $250 million IPO, with $35 million earmarked for the development of its RIPK1 inhibitor for the treatment of Alzheimer’s. And just last month, David Michelson, who led the BACE inhibitor program at Merck, signed on with Proclara Biosciences, where he will oversee the clinical development of its lead candidate, which targets beta-amyloid and tau proteins.

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