Long chain amyloid a drug target?

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Scientists have identified a new, longer species of the amyloid
b-peptide that has the potential to be a new target for the
treatment of Alzheimer's disease The discovery serves as a basis
for treating one of the characteristic features of Alzheimer's
disease for which there is currently no effective treatment.

The discovery aims to deal specifically with the large deposits of amyloid b-peptides in the brain that have been associated with the deterioration of the brain's functions. These amyloid â-peptides are derived from a large amyloid precursor protein through a series of cleavage events.

Dr. Xuemin Xu, lead researcher at The University of Tennessee, and his colleagues, discovered a new species of amyloid â-peptide that is 46 amino acids long, called Aâ46. This Aâ46 peptide is produced by ã-secretase enzyme at a novel cleavage site, which also happens to be the site of a mutation found in early-onset familial Alzheimer's disease called the APP717 or London mutation.

Generally, amyloid â-peptides are around thirty-nine to forty-three amino acids long. Studies have shown that the longer amyloid â-peptides are more amyloidogenic and more pathogenic than the shorter ones

While the exact pathogenic role of amyloid â-peptide in Alzheimer's disease has not yet been established, accumulating evidence supports the hypothesis that amyloid â-peptide production and deposition in the brain could be a causative event in Alzheimer's disease.

The discovery takes a different approach to treating this disorder. Neuroprotection is seen as a better alternative to acetylcholinesterase inhibitors which treat the symptoms of the disease and are the most viable form of pharmaceutical treatment currently available.

While sufferers show improvements when taking acetylcholinesterase inhibitors, their mechanism of action does not correct the basic pathology of the disease, the beta amyloid deposits or neurofibrillary tangles that are the very focus of this study.

"The amyloid precursor protein may function as a receptor or growth factor precursor,"​ said Xu. "Recent studies also suggest that the intracellular C-terminal domain of the amyloid precursor protein may function as a transcription factor."

Under normal conditions, cleavage first by the enzyme á-secretase and then by ã-secretase results in a short peptide called p3, and an intracellular C-terminal domain, none of which are amyloid forming.

However, amyloid precursor protein can be processed by the enzymes â-secretase and ã-secretase to produce a soluble ectodomain along with the full-length amyloidogenic amyloid â-peptide and the intracellular C-terminal domain.

Dr. Xu explained that amyloid â-peptide itself could be toxic to synapses and the accumulation of amyloid â-peptide could initiate a series of events contributing to cell death, including activation of cell death programs, oxidation of lipids and disruption of cell membranes, an inflammatory response, and possibly neurofibrillary tangle formation, which is a close correlate of neuron loss.

"These novel findings provide information important for the strategy of prevention and treatment of Alzheimer's disease, aimed at the design of ã-secretase inhibitors,"​ commented Dr. Xu.

"Since amyloid â-peptide is produced by the sequential actions of â- and ã-secretases, inhibition of these secretases to reduce the production of amyloid â-peptide is believed to be one of the more promising avenues of treatment of the disease. To date, more than one dozen ã-secretase inhibitors have been developed or identified."

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.

With increasing patient numbers and the limitations of available therapies, the Alzheimer's disease market is an attractive investment with huge unmet need. Although it occupies a small share of the total CNS market it is currently experiencing massive growth. Alzheimer's disease market in the seven major markets is worth $4.7 billion (€3.8 billion) and will increase to $6.1 billion by the year 2005 and $ 7.8 billion by the year 2010.

There are an estimated 18 million people in the world with dementia, according to the charity Alzheimer's Disease International, which estimates that by 2025 this figure could increase to 34 million. And finding a treatment that could delay onset by just five years could reduce the number of individuals with Alzheimer's disease by nearly 50 per cent after 50 years.

The research appears as the "Paper of the Week" in the December 3 issue of the Journal of Biological Chemistry​, an American Society for Biochemistry and Molecular Biology journal.

Related topics: Preclinical Research

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