Alzheimer’s Disease and Effectiveness of Amyloid-β Aggregation Blockers

Alzheimer’s disease results from the deposit of something called Amyloid-ß protein peptides in the brain. These proteins collect over a period of time resulting in the formation of plaque. Some substances are thought to prevent the collection of Amyloid-ß peptides by binding to them. In the present study, researchers have explained two simple in vitro tests, the microplate method and the immunohistochemical method; these tests measure the efficacy of Amyloid-ß peptide collection blockers. Using these techniques, researchers evaluated the efficacy of various agents that are believed to slow the progression of Alzheimer’s disease.

Amyloid-ß peptides are produced because of mutations in some genes. Such mutations can be artificially induced in laboratory animals. They are used as models to study the efficacy of various substances in the prevention and cure of Alzheimer’s disease. So far, many substances have been shown to inhibit the aggregation of Amyloid-ß peptides. However, none of them has been proven to be efficacious in patients and hence, they are yet not permitted for use in regular treatment. In the present study, researchers developed two novel techniques to examine the Amyloid-ß peptide binding capacity of substances such as PGG, epigalocatechin gallate, diclofenac, resveratrol, myo-inositol, rhamnose, emodin, and the extracts of garlic, spirulina, cinnamon, ginger, blueberries and turmeric.

* In the microplate assay, wells coated with synthetic Amyloid-ß peptide were incubated with fluorescent tagged Amyloid-ß peptide along with the substances to be tested. Among the tested substances, seven food products were included. These were blueberries, ginger, rhubarb, garlic, cinnamon, spirulina, and turmeric. Presence of fluorescence indicated the inability of the test substance to block the aggregation of Amyloid- ß peptide.
* In the immunohistochemistry test, researchers used the brains of transgenic mice and humans who had died of Alzheimer’s disease. Thin sections of brain tissue were placed on slides. They were first treated with antibodies against the Amyloid-ß peptide (which was tagged with a dye) to find the ability of the antibody to bind to Amyloid-ß peptide. In the second step, tissue sections were pretreated with the test substance, and then the first step was repeated.
* If the test substance had the ability to bind to Amyloid- ß peptide in brain tissue, then dye tagged anti-Amyloid-ß antibody would not bind to it, thus resulting in lack of color in the tissue sections. This would confirm the ability of the test substance to prevent aggregation of Amyloid-ß peptides.

* Both the methods yielded comparable results. On testing all the substances that were earlier believed to possess Amyloid-ß peptide-binding activity, most of them showed very low binding affinity that was clinically ineffective.
* The substances that showed marginal binding affinity to Amyloid-ß peptide were ginger, blueberries, rhubarb, turmeric, cinnamon, resveratrol, S-diclofenac, epigallocatechin gallate (EGCG), 1,2,3,4,6-penta-O-galloyl-b-D-glucopyranose (PGG), and extracts of spirulina.
* Curcumin, garlic extract, ginkgolide A, rhamnose, rhein, myo-inositol, valproic acid, emodin, caryophellene, tramoprosate, and scyllo-inositol failed to bind to Amyloid-ß peptide.

Shortcomings/ Next steps
Many compounds that are believed to be effective against Alzheimer’s disease were found to be inactive through this study. The authors believe that other mechanisms might have been responsible for their beneficial effects, which couldn’t be tested by the assays used in this study. Future studies should focus on examining these mechanisms.

In the present study, researchers have described two simple in vitro tests to assess the efficacy of Amyloid-ß peptide aggregation blockers. These tests can be carried out rapidly and unlike in vivo tests done directly on patients, they do not cause inconvenience to the participants. This study has also shown that none of the putative blocking agents has sufficient affinity to Amyloid-ß peptides, so that it can be used for the treatment and prevention of Alzheimer’s disease. Moreover, these agents will have to cross the blood-brain barrier before reaching the brain, which is normally not possible for large molecules.

For More Information:
Simple In Vitro Assays to Identify Amyloid-ß Aggregation Blockers for Alzheimer’s Disease Therapy
Publication Journal: Journal of Alzheimer’s Disease, 2010
By Jian-Ping Guo; Sheng Yu; University of British Columbia, Canada

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