Significant progress has been made in recent years toward understanding the mechanisms involved in the proteolytic processing of APP. However, further research is required to fully characterize the a-, P-, and y-secretases as b-secretase inhibition g-secretase inhibition


---- sAPPa non-amyloidogenic a-secretase activation

Fig. 2. Secretases as potential targets for therapeutic intervention in Alzheimer's disease (AD). In the amyloidogenic pathway, APP is processed by the P- and y-secretases to produce the neurotoxic AP peptide, whereas in the nonamyloidogenic pathway APP is processed by a-secretase to generate the neuroprotective sAPPa. In AD, there may be an imbalance between the amyloidogenic and nonamyloidogenic pathways, resulting in an increase in AP production and a decrease in sAPPa. Thus, compounds that either inhibit P- and y-secretase or activate a-secretase might have therapeutic potential therapeutic targets in AD. The ultimate test of any therapy will be whether it can halt or reverse the pathological process, and thus be considered as disease modifying, and whether this can be translated into clinical benefits for patients. As with other multifactorial diseases, it might be that a variety of therapeutic approaches targeting different aspects of the disease pathology will be necessary, and thus the secretases may be just some of the pharmacological targets in AD.

Acknowledgments. The financial support of the Medical Research Council of Great Britain and the Health Foundation is gratefully acknowledged. The authors are members of the Yorkshire Centre in the Alzheimer's Research Trust's Alzheimer's Disease Research Centre Network.

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