Editorial [Hot Topic: Drug Targets in Alzheimer's Disease (Executive Editors: G. Munch and G. Stuchbury)]

Alzheimer's disease (AD) is the most common cause of dementia, affecting more than 30% of the population over 85 years of age. In 2002, the estimated cost of dementia in Western countries was about 1% of GDP, by 2050, this is expected to increase to about 3%. The development of neuroprotective pharmacological strategies is an important task for the research community. AD is characterized by two characteristic lesions, amyloid plaques and neurofibrillary tangles, which are present in high numbers in the grey matter of affected brain areas. Neurofibrillary tangles are intracellular deposits formed by hyperphosphorylated and extensively crosslinked tau protein. Tau is a microtubule-associated protein that regulates a variety of properties of neuronal microtubules, especially their stability and orientation. In AD, however, tau is hyperphosphorylated and forms fibrillar inclusions. Presumably this leads to neuronal dysfunction by disturbing cytoskeletal functions of neurons, resulting in abnormal axons and therefore impaired axonal transport. Senile plaques are the second characteristic hallmark in AD sufferers. These extracellular protein deposits are mainly composed of beta-amyloid peptide (Aβ) which forms b-sheeted fibrils that become insoluble. Aβ is derived from the β-amyloid precursor protein (APP), an integral membrane protein that is processed by β- and γ-secretases. In a variety of cell culture models, Aβ has been shown to cause toxicity to neurons by various mechanisms, many of which involve oxidative stress. Inflammation, as evidenced by the activation of microglia and astroglia, is another hallmark of AD. Inflammation, including the induction of superoxide production ("oxidative burst"), is an important source of oxidative stress in AD patients. The inflammatory process occurs mainly around the amyloid plaques and is characterized by pro-inflammatory substances released from activated microglia. Reactive oxygen species (ROS) are the most prominent molecules in the inflammatory process, along with prostaglandins, IL-1b, IL-6, M-CSF and TNF-α. In light of the many pathological hallmarks of the disease, selecting a therapeutic target and designing appropriate pharmacological strategies appears to be a very complex and nearly impossible task. This issue of Current Pharmaceutical Design combines contributions from some of the world leaders in the filed of AD therapy and presents a kaleidoscope of theories and approaches, as well as original data mixed with expert reviews. In the first article, Taisuke Tomita and Takeshi Iwatsubo [1] intensively review g-secretase, the pivotal enzyme in generating the C terminus of Aβ. Their manuscript informs the reader on recent progress in g-secretase biology, which has shed substantial light on the proteolytic mechanism, regulation and composition of this unusual enzyme, as well as the recent development of inhibitors of γ-secretase activity.....