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

Abstract

Background: According to the ‘amyloid cascade hypothesis’ of Alzheimer's disease (AD), abnormal processing of beta-amyloid precursor protein (βAPP) into toxic amyloid beta (Aβ)-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 Aβ-peptide 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at various websites: Alzheimer Research Forum; individual drug company databases; Medline; Pharmaprojects database; unpublished research; inter-University research communications.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 βAPP processing, and the latest pharmacological strategies have used selective Aβ-peptide-lowering agents (SALA) to provide therapeutic benefit against Aβ-initiated neurodegenerative pathology. Currently, dedicated anticholinesterase, glutamatergic agonist and Aβ-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 Aβ-peptides. The long-term benefits or complications of statin-based therapies for use in the clinical management of AD are not known.

Keywords::

• Alzheimer's disease
• amyloid beta (Aβ) peptides
• beta-amyloid cleavage enzyme 1 (BACE-1
• β-secretase)
• beta-amyloid precursor protein (βAPP)
• gamma secretase (γ-secretase)
• neurodegenerative disease
• presenilin-1 (PS1)
• secretase
• selective Aβ42-lowering agents (SALA)
• statins

Acknowledgements

The authors would like to thank Darlene Guillot (Louisiana State University Health Sciences Center, New Orleans) for the artwork for Figure 1.