Treatment reduces levels of toxic beta-amyloid in mouse brain cells

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

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

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

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The poster, titled “Development of novel gamma-secretase modulators for the treatment of Alzheimer’s diseasewas presented at the second Swedish meeting for research on Alzheimer’s disease. Maria Backland, PhD, Senior Scientist at AlzeCure, gave the presentation.

Alzheimer’s disease is characterized by the clumping together of various types of amyloid-beta protein fragments, including toxic amyloid-beta 42. These clumps begin to form early – sometimes years before symptoms appear – and lead to progressive worsening of nerve cell function disorders. and ultimately cell death.

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

AlzeCure’s research platform, Alzstatin, aims to develop compounds that modulate gamma-secretase activity, with the aim of preventing the formation of toxic amyloid-beta clusters.

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

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

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

The results showed that treatment with AC-0027875 effectively resulted in a more than 50% reduction in amyloid beta 42 levels in these cell cultures. Similar results 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 administered 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 (brain and spinal cord). Finding compounds that can cross this barrier has been a long-standing challenge in developing treatments for brain disorders.

Similar to 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 the 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 effectively, which we have also shown in these new preclinical studies,” Jönsson added.

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

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