Amyloid beta (Aβ) peptide modulators and other current treatment strategies for Alzheimer’s disease (AD)

Abstract

Introduction: Alzheimer’s disease (AD) is a common, progressive neurological disorder whose incidence is reaching epidemic proportions. The prevailing “amyloid cascade hypothesis,” which maintains that the aberrant proteolysis of beta-amyloid precursor protein (βAPP) into neurotoxic amyloid beta (Aβ) peptides is central to the etiopathology of AD, continues to dominate pharmacological approaches to the clinical management of this insidious disorder. This review is a compilation and update on current pharmacological strategies designed to down-regulate Aβ42 peptide generation in an effort to ameliorate the tragedy of AD.

Areas covered: This review utilized online data searches at various open online-access websites including the Alzheimer Association, Alzheimer Research Forum; individual drug company databases; the National Institutes of Health (NIH) Medline; Pharmaprojects database; Scopus; inter-University research communications; and unpublished research data.

Expert opinion: Anti-acetylcholinesterase-, chelation-, N-methyl-D-aspartate (NMDA) receptor antagonist-, statin-, Aβ immunization-, β-secretase-, γ-secretase-based, and other strategies to modulate βAPP processing, have dominated pharmacological approaches directed against AD-type neurodegenerative pathology. Cumulative clinical results of these efforts remain extremely disappointing, and have had little overall impact on the clinical management of AD. While a number of novel approaches are in consideration and development, to date there is still no effective treatment or cure for this expanding healthcare concern.

Keywords::

• Alzheimer’s disease (AD)
• amyloid beta (Aβ) peptides
• amyloidosis
• beta-amyloid cleavage enzyme 1 (BACE-1)
• beta-amyloid precursor protein (βAPP)
• chelation therapy
• immunological strategies
• neurodegenerative disease
• presenilin-1 (PS1)
• secretase
• statins
• γ-secretase

Acknowledgements

Thanks are extended to P Alexandrov, B Bhattacharjee, C Eicken, PE Fraser, C Hebel, JM Hill, TPA Kruck, ME Percy, AI Pogue, W Poon, E Rogaev, T Saing and Y Zhao for helpful discussions and ongoing collaboration, and to Darlene Guillot for expert technical assistance.