Editorial- Update on Current Alzheimer Research

Current Alzheimer Research presents the second issue of its third volume, which comprises nine articles from both primary research and review work. These articles report a combination of mechanism-based and clinicallyoriented translational studies that cover a wide range of Alzheimer's disease (AD) research from the cholinergic model; the role of amyloid, tau protein and metals; to oxidative stress. The present issue reports nine articles addressing the most exciting and relevant topics in the field of AD. Two papers discuss interactions of the amyloid beta peptide (Aβ)/Aβ precursor protein (APP) with other cellular systems, two papers highlight studies on anticholinesterase (AChE) inhibitors, one paper each presents studies on tau protein phosporylation, apolipoprotein E (APOE) genotype, mild cognitive impairment (MCI) and a promising treatment strategy. In addition, there is an interesting 'Commentary' on angiotensin converting Enzyme (ACE) inhibitor. Standridge presents (p 95-108) a comprehensive view of the neuropathophysiological mechanisms for AD, involving several vicious cycles. A number of interactive systems that each alone or together, once set in motion, amplify their own processes, thereby accelerating the development of AD. Hypoperfusion, the defective clearance of amyloid, and resultant increase in amyloid deposition represent an example of vicious cycle. In addition, AD symptoms most likely result from aberrant nerve cell signaling and synaptic failure rather than nerve cell death, which follows and accelerates the initial pathology of AD. Heese and Akatsu summarize (p 109-121) both physiological and pathophysiological functions of APP and its cleavage product Aβ, based on recent data from genomics, proteomics and molecular genetics. This review provides an insight into interaction of APP and Aβ with other cellular systems present and their roles in the pathogenesis of AD. In addition to Aβ deposition, AD is characterized by the presence of paired helical filaments, mostly made up of hyperphosphorylated tau protein. However, the mechanism for tau phosphorylation and its interaction with metals are poorly understood and is an active field of current research. One of the important kinases that modifies tau protein is called GSK3. Herein, Gómez-Ramos and colleagues (p 123-127) discuss the effect of two metals, lithium and tungstate, on GSK3 (or tau I kinase) activity, and its important implications for AD. Mechanistic studies lead to the development of potential treatment strategies. This is important because currently available drugs transiently relieve some symptoms of AD but have no significant effects on the progression of the disease. Based on the prevailing "amyloid" hypothesis, preventing the formation of "bioactive" Aβ or inactivating previously formed bioactive Aβ is becoming a promising approach for treating AD. Liu and Schubert (p 129-135) describe a cell-based assay for detecting bioactive Aβ to screen for drugs that can inactivate bioactive Aβ. They discuss several promising compounds that can inactivate bioactive Aβ species, and this constitutes a promising approach for the potential treatment of AD. Research on currently available and FDA approved AChE inhibitor drugs reveal interesting results. Doganay and colleagues report (p 137-145) pharmacological manipulation of the vasoconstrictive effects of Aβ peptides by donepezil and rivastigmine. They postulate that such AChE inhibitor drugs mediate these vascular modulatory effects via an action on Aβ-mediated vasoconstrictor mechanisms rather than an independent action on endothelial or smooth muscle cell mediated responses. At the clinical level, Behl and colleagues determined if there are differential treatment effects of second-generation AChE inhibitors over one year. They report (p 147-156) that cholinesterase inhibitors slow decline in executive functions, rather than memory in AD based on this observational study. Notably, executive, language and visuospatial functions, rather than memory, seems to be more amenable to stabilization over one year by cholinesterase inhibitors in AD. In the area of genetic risk factors for AD, Sabbagh and colleagues report (p 157-160) studies on the effect of the APOE genotype on the lipid profile in AD. They report that APOE gene status has minimal influence on either the lipid panel or mean age of onset for AD. Interestingly, APOE gene dose influences the lipid panel with APOE ɛ2/2, and ɛ2/3 having significantly better lipid panels and later age of onset. In the area of predictors for AD, current research suggests that half of MCI patients convert to dementia within 3 years. Since not all patients convert to......