Editorial [Hot Topic: Alzheimers's Disease, Dementia and Cognitive Decline (Executive Editors: J.E. Starrett, Jr. and G.S. Poindexter)]

Alzheimer's Disease (AD) and its associated morbidity continues to be a devastating condition for patients afflicted with this ailment, as well as the family and caregivers of patients. Although great strides have been made with respect to understanding the etiology associated with AD, it still remains a large unmet medical need, affecting nearly one in ten individuals over the age of 65, and nearly one in two persons by age 85 [1]. This issue of Current Pharmaceutical Design addresses AD, dementia and cognitive decline. In organizing this edition, we have sought out experts in the pharmaceutical industry who are actively pursuing approaches to treat these afflictions. As a treatment for cognitive decline, Rose and coworkers [1] discuss inhibition of phosphodiesterases (PDEs). A rationale is presented for the inhibition of PDEs as a second messenger system to inhibit cyclic adenosine monophosphate (cAMP). cAMP plays a key role in biochemical processes that regulate the process of memory consolidation. The pathophysiology of AD and the immune response is discussed by Nelson [2]. Transgenic animals are being developed which explore this relationship. The relative merits of transgenic animals, immunotherapy, and their relevance to simplifying clinical trials are detailed. Clader and Wang [3] approach the treatment of the loss of cognitive function associated with AD by studying the loss of cholinergic activity. In an effort to increase cholinergic function, regulation of the muscarinic receptors has been studied. Stimulation of the muscarinic M1 receptor by M1 agonists improves cognitive function. In contrast, antagonism of the M2 receptor improves cognitive function. The relative structure activity relationships of agonists and antagonists of the receptors are presented. The paper of Churcher and Beher [4] provide an account of the current approaches to treat AD by decreasing amyloid β (Aβ)-associated toxicity by inhibiting gamma secretase, an enzyme responsible for the final step in Aβ synthesis. The structure activity relationship of inhibitors is discussed, as well as the potential pitfalls associated with this approach. Inhibitors of gamma secretase have also been shown to inhibit Notch processing, resulting in peripheral toxicity. Differentiating between these two processes may prove to be a difficult task. Thompson, Bronson and Zusi [5] present a promising alternative to the inhibition of gamma secretase for decreasing central Aβ levels, by inhibition of β-secretase (BACE) in AD patients. The rationale for BACE inhibition is presented, as well as detailed structure activity relationships. We would like to thank all of the authors for their commitment in writing these reviews. Their work will contribute to a greater understanding of AD and will hopefully speed the discovery and development of treatments for this important therapeutic target. References [1] Rose GM, Hopper A, De Vivo M, Tehim A. Phosphodiesterase Inhibitors for Cognitive Enhancement. Curr Pharm Design 2005; 11(26): 3329-3334. [2] Nelson RB. The Dualistic Nature of Immune Modulation in Alzheimer's Disease: Lessons from the Transgenic Animals. Curr Pharm Design 2005; 11(26): 3335-3352. [3] Clader JW, Wang Y. Muscarinic Receptor Agonists and Antagonists in the Treatment of Alzheimer's Disease. Curr Pharm Design 2005; 11(26): 3353-3361. [4] Churcher I, Beher D. g-Secretase as a Therapeutic Target for the Treatment of Alzheimer's Disease. Curr Pharm Design 2005; 11(26): 3363-3382. [5] Thompson LA, Bronson JJ, Zusi FC. Progress in the Discovery of BACE Inhibitors. Curr Pharm Design 2005; 11(26): 3383-3404.