Alzheimer's disease exists in two forms, early onset familial disease (FAD) and late onset disease. Four million Americans currently suffer from the condition and experts estimate that 22 million people around the world will be afflicted by 2025. Until recently, researchers had almost no understanding of the disorder's causes and it still lacks preventive or curative therapies. The amyloid hypothesis suggests that the process of beta amyloid protein fibrillogenesis is responsible for triggering a cascade of physiological events that contribute directly to the initiation and progression of Alzheimer's disease. Hence the identification of therapeutic strategies that prevent the accumulation or the toxicity of beta amyloid represents a major target for the pharmaceutical industry. The exact reason for the neutoxic effects of beta amyloid is unclear but altered calcium regulation, immune stimulation and/or mitochondrial damage have all been proposed as causative factors. The latter is likely to result in increased levels of free radicals and hence oxidative damage to DNA, lipids and proteins has been detected by a range of assays in post-mortem tissues from patients with neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including apomorphine. A collaboration of Brigham and Women's Hospital and Harvard Medical School researchers have recently advanced the development of apomorphine homologues for the treatment of Alzheimer's disease. Specifically they describe a new class of small molecule derivatives of apomorphine that inhibit beta amyloid aggregation. These molecules were found to interfere with beta amyloid-40 fibrillization. SAR studies demonstrate that the 10,11-dihydroxy substitutions of the D-ring of apomorphine are required for the inhibitory effectiveness of these apomorphines, and methylation of these hydroxyl groups reduces their inhibitory potency. The ability of these small molecules to inhibit beta amyloid fibril formation appears to be linked to their tendency to undergo rapid autoxidation, suggesting that the autoxidation product(s) act(s) directly or indirectly on beta amyloid to inhibit its fibrillization. The inhibitory properties of the compounds presented suggest a new class of small molecules that could serve as a scaffold for the design of more efficient inhibitors of beta amyloid amyloidogenesis in vivo.

December, 2002

Adapted from Lashuel et al, J Biol Chem 2002 Nov 8;277(45):42881-90

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