New technique blocks Alzheimer's plaque build-up

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Related tags: Small molecule, Protein, Alzheimer

A new therapeutic technique based on a small molecule working in
tandem with a larger protein has been shown to block accumulation
of the brain-clogging amyloid protein seen in Alzheimer's disease,
raising the possibility of a new effective drug treatment.

The approach centres on a new strategy that reduces the neurotoxic amyloid protein aggregates critical in the development of the disease and overcomes the challenge in drug design of the limited ability of molecules small enough to enter a cell to interfere with interactions between much larger proteins.

Pharmaceutical companies have long tried to develop inhibitors of the amyloid beta peptide, individual units that form the amyloid protein chains that build up in the brain. The universal approach has been to screen for small molecules that bind to those aggregates and hope they would prevent further aggregation.

However, in most cases the molecules fit right inside the build up and do not prevent aggregation at workable concentrations.

The problem faced by pharmaceutical industry is two fold as the complexities of protein interactions are also called into play. Protein interactions represent the binding of two large matched surfaces. A drug originating from a small molecule is only a tiny fraction of the size of those surfaces. Proteins would simply bind around the drug, rendering them useless.

The vast majority of current research focuses on the cerebral cortex of Alzheimer's patients, which contain large protein aggregates called beta-amyloid peptide, a small protein. This peptide collects in the brain of Alzheimer's patients and forms protein deposits, which can damage and even destroy the sensitive nerve cells.

This latest research concentrates on interfering with protein-protein interactions by designing small molecules with two binding sites. One binds to the protein which interaction was to be blocked. The other would selectively bind to a much larger protein called a chaperone. Chaperone proteins are present in cells and serve as 'helper' molecules that guide proteins to their proper functional location in the cell.

Lead author of the study Jason Gestwicki, constructed a series of small 'linker' molecules that would attach to a molecule called FKBP, a family of chaperone proteins Gestwicki attached the other end of the linker to a molecule called Congo red, which is known to selectively bind to Aß peptide.

In test-tube studies, the small 'linker' molecules blocked the growth of amyloid aggregates from their Aß peptide components. In additon these molecules inhibited growth of the shorter amyloid chains, which are thought to be toxic to neurons.

The team, led by Howard Hughes Medical Institute scientist Gerald Crabtree, also found by varying the linker molecules, they could optimise pharmaceutical properties such as its ability to penetrate the cell membrane to enter the cell.

Crabtree said the next step would be to test the molecules on mouse models of Alzheimer's disease, to determine whether the molecules have a clinical effect on progression of the disease.

The researchers are hopeful this therapy might complement other treatments currently being tested for Alzheimer's disease. These include anti-inflammatory treatments to prevent neuronal cell death from toxic aggregates.

Scientists at Berlex Pharmaceuticals, found a receptor called CCR1, usually found on white blood cells, is also present in the brains of patients with Alzheimer's, accumulating in swollen nerve fibres. Berlex initiated a clinical study to determine if targeting CCR1 with a radiolabelled, small molecule CCR1-antagonist, called BX471, had potential as a brain-imaging biomarker. Preliminary results of the study are yet to be available.

Research into vaccines that trigger antibodies to rid the brain of plaque have become popular too. Using a harmless version of the Herpes simplex virus, scientists at the University of Rochester Medical Centre put into mice a payload of genetic material designed to stimulate specific elements of the host immune response and cut out the toxic side effects seen in a previous study in people of a vaccine against Alzheimer's developed by Elan and Wyeth.

Inhibitors of aberrant molecular signalling pathways in Alzheimer's using gene therapy also brings a potential lead that might make some much-needed headway.

The new technique, which used a gene therapy agent to deliver a drug containing nerve growth factor (NGF) to the patient, was attempted by scientists at Rush University.

The new technique used CERE-110 as the gene therapy agent which carries the active part of the drug, the NGF gene. This human DNA strand codes for the NGF protein, a natural substance that exerts regeneration effects where neurons are degenerating, halting cell death and reverse cell atrophy, the hallmarks of Alzheimer's.

The new drug is being used by researchers at Rush as part of a Phase I study that commenced in September to evaluate its safety and tolerability using two different doses. Memory and cognitive function will also be assessed regularly during the two-year period of the study.

Related topics: Preclinical Research, Ingredients

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