Emerging amyloid beta (Aβ) peptide modulators for the treatment of Alzheimer's disease (AD)

Background: According to the amyloid cascade hypothesis' of Alzheimer's disease (AD), abnormal processing of beta-amyloid precursor protein (PAPP) into toxic amyloid beta (A beta)-peptides is central to the etiopathology of this uniquely human brain disorder. Objective: To review current AD drugs, pharmacological approaches and strategies aimed at modulating A beta-pepticle generation and/or aggregation in the treatment of AD. Methods: Data searches at various websites: Alzheimer Research Forum; individual drug company databases; Medline; Pharmaprojects database; unpublished research; inter-University research communications. Results/conclusion: Considerable research effort has focused on secretase-mediated mechanisms of PAPP processing, and the latest pharmacological strategies have used selective A beta-peptide-lowering agents (SALA) to provide therapeutic benefit against A beta-initiated neurodegenerative pathology. Currently, dedicated anticholinesterase, glutamatergic agonist and A beta-peptide immunization have had little impact in the clinical treatment of AD. One unexpected benefit of statins (HMG-CoA inhibitors), besides their cholesterol lowering abilities, has been their ancillary effects in potentiating the enzymatic mechanisms that generate A beta-peptides. The long-term benefits or complications of statin-based therapies for use in the clinical management of AD are not known.