This material is the copyright of the original publisher. Unauthorised copying and distribution is prohibited. Disease-Modifying Approach to the Treatment of Alzheimer's Disease From a-Secretase Activators to c-Secretase Inhibitors and Modulators

In the last decade, advances in understanding the neurobiology of Alzheimer’s disease (AD) have translated into an increase in clinical trials assessing various potential AD treatments. At present, drugs used for the treatment of AD only slightly delay the inevitable symptomatic progression of the disease and do not affect the main neuropathological hallmarks of the disease, i.e. senile plaques and neurofibrillary tangles. Brain accumulation of oligomeric species of b-amyloid (Ab) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being made to identify drugs able to interfere with proteases regulating Ab formation from amyloid precursor protein (APP). Compounds that stimulate a-secretase, the enzyme responsible for non-amyloidogenic metabolism of APP, are being developed and one of these, EHT-0202, has recently commenced evaluation in a phase II study. The discovery of inhibitors of b-secretase (memapsin-2, b-amyloid cleaving enzyme-1 [BACE-1]), the enzyme that regulates the first step of amyloidogenic