Treatment Lowers Toxic Amyloid-beta Levels in Mouse Brain Cells

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by Lindsey Shapiro PhD |

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An investigational gamma-secretase modulator designed for the treatment of Alzheimer’s disease led to an efficient and long-lasting reduction of toxic amyloid-beta 42 peptide in cell cultures and mouse brain cells, according to data from a recent study.

In mice, the compound, called AC-0027875, was also able to penetrate the brain in high concentrations, which is an important feature of effective therapies for Alzheimer’s, according to the compound’s developer, AlzeCure Pharma.

“AC-0027875 has a promising profile as a potential anti-amyloidogenic therapy. Additional studies to fully characterize AC-0027875 in vivo [in live animals] are in progress,” AlzeCure wrote in a poster presentation of the findings.

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The poster, titled “Development of novel gamma-secretase modulators for the treatment of Alzheimer’s disease,” was presented at the second Swedish Meeting for Alzheimer Research. Maria Backland, PhD, a senior scientist at AlzeCure, gave the presentation.

Alzheimer’s disease is characterized by the clumping of various types of amyloid-beta protein fragments, including the toxic amyloid-beta 42. These clumps begin to form early on — sometimes many years before symptoms emerge — and lead to progressively worsening impairments in nerve cell function and ultimately cell death.

Normally, amyloid-beta proteins are formed when the amyloid-beta protein precursor (APP) is cleaved down into smaller fragments. This process is mediated by an enzyme called gamma-secretase.

AlzeCure’s research platform, Alzstatin, is aimed at developing compounds that modulate gamma-secretase activity, with the goal of preventing the formation of toxic amyloid-beta clumps.

The company says that such modulators have been shown to prevent amyloid-beta 42 formation and instead stimulate the production of shorter amyloid beta forms that are less likely to aberrantly clump together, such as amyloid-beta 38. These shorter forms also restrict the effects of amyloid-beta 42 that has already been formed.

According to AlzeCure, the modulators may be able to act on disease progression or prevent disease onset in presymptomatic Alzheimer’s patients if the treatment is given early enough.

In the study, the researchers investigated the effects of AC-0027875 in cell cultures containing a mutant form of APP that is prone to overproduce toxic amyloid-beta.

Results showed that treatment with AC-0027875 efficiently led to a more than 50% reduction in amyloid-beta 42 levels in these cell cultures. Similar findings were observed in cell cultures of mouse brain cells.

When a single, oral dose of the therapy (60 micromoles per kilogram of body weight) was given to live mice, results showed that AC-0027875 could successfully cross the blood-brain barrier and reach high concentrations in the brain — which is the target organ of the therapy.

The blood-brain barrier is a selective layer of cells that serves as a barrier to the central nervous system (the brain and spinal cord). Finding compounds that are able to cross this barrier has been a long-standing challenge in the development of treatments for brain disorders.

Similarly to the observations in cell cultures, AC-0027875 also led to significant reductions in amyloid-beta 42 levels in mouse brain tissue.

The disease-modifying drug therapy “is being developed to be particularly well-suited for early, preventive treatment of Alzheimer’s disease,” Martin Jönsson, CEO of AlzeCure, said in a press release.

“Treatment with a small-molecule substance … has advantages in that it can be optimized to cross the blood-brain barrier in an efficient way, something we have also shown in these new preclinical studies,” Jönsson added.

The results highlight the potential for AC-0027875 or other gamma-secretase modulators to prevent amyloid-beta 42 buildup in Alzheimer’s disease. A next step will be to further characterize the treatment’s disease-modifying effects in mouse models, AlzeCure reported.