β-amyloid peptide as a target for treatment of Alzheimer's disease

Alzheimer's disease is a progressive neurodegenerative disorder characterised by a series of biochemical and histological changes although the net of relations and its initial cause is far from being fully understood. The amyloid hypothesis points out the pathological processing of a physiologically normal protein, the amyloid precursor protein, to neurotoxic forms of amyloid P-peptide as the origin of the cascade of biochemical changes that lead to Alzheimer's disease. Normal APP processing involves three proteases, alpha-, beta- and gamma-secretase, to yield physiological amyloid fragments. Familial Alzheimer's disease patients exhibit an increased activity of beta- and gamma-secretases, resulting in higher than average levels of small amyloid fragments, of 40 or 42 amino acids (Abeta(40) and Abeta(42), respectively). These newly formed Abeta(40) and Abeta(42) may suffer a conformational change followed by aggregation into fibrils and finally deposition as senile plaques in a complex process named fibrillogenesis, which is associated with neurotoxicity. Modulation of this multistep process is a reasonably hopeful approach for the treatment of Alzheimer's disease. In a general sense, this approach can be divided in three groups: first, modulating the production of Abeta promoting the non-amyloidogenic route; second, inhibiting fibrillogenesis and third, by immunisation techniques, enhancing the formation of anti-Abeta antibodies in order to mark fibrils and plaques as targets for microglial cells.