Current Alzheimer Research - Volume 4, Issue 1, 2007

Current Alzheimer Research enters the fourth year of successful publication with a great sense of fulfilling our mission. During the last year, five issues of its third volume have been completed and published on time. The third volume featured a total of 65 articles in addition to Editorials.These articles, comprising primary research articles and review papers, were written and peer-reviewed by experts in neuroscience and Alzheimer's disease (AD). Current Alzheimer Research remains an international journal as exemplified by contributions from researchers belonging to 19 countries: Australia, Austria, Belgium, Canada, China, France, Germany, India, Israel, Italy, Japan, Netherlands, Singapore, Spain, Sri Lanka, Taiwan, UAE, UK and the USA. Diversity of the experimental models discussed in the last volume, which ranged from cell culture-based to animal and human studies is also worth noting. Success of the journal is reflected in its acceptance for listing in PubMed/MEDLINE and other databases. The journal is currently accessible via online (http://www.bentham.org/car/) and abstracts of each article are freely available on the journal's website The focus of Current Alzheimer Research continues to be reporting mechanistic, drug-related and translational-based advances in Alzheimer's disease and related disorders. A wide range of topics in AD research, including amyloid biogenesis, brain imaging, immunotherapy, genetics, oxidative stress and tauopathy have been discussed by world renowned experts in the area, and several unique and controversial topics have been presented to encourage novel directions. In addition, the journal continues to publish results from clinical drug trials, including adequately-justified, evidencebased negative data. Covering the entire AD field is not an easy task, nor should it be our goal. For example, during the last single year alone, AD has captured over 3,800 citations on PubMED/MEDLINE search. Thus, the necessity of timely dissemination of this knowledge is of great importance. Although Current Alzheimer Research covers a small fraction of primary research, our review articles present a comprehensive overview of selected interesting topics, which makes an important contribution and provide a great resource to the AD field. In the current fourth volume, with at least 5 different issues, Current Alzheimer Research gears up to present a wide range of themes in the forms of critical review articles and original research reports, which are expected to address the neurobiology of AD, analyze potential drug targets, and elucidate novel therapeutic strategies. The journal plans to cover research topics in current molecular, genetic, and in vivo models. Like previous years, the 4th volume will occasionally bring special issues written by experts on different “Hot Topics” of AD. Indeed, the next issue of the journal will be a special ‘Hot Topic’ issue entitled “Exploring the Links between Obesity and Alzheimer Research” (Guest Editor: Dr. Suzana Petanceska). Issue 1 of the 4th volume contains 8 articles, which address both the most interesting and relevant topics in the field of AD and neurodegenerative disorders and the potential utility of several valid targets for the therapy of AD. The present issue is focused on understanding signaling pathways, the role of different hormones and growth factors and the relevance of each in therapeutic strategies. However, the converging connection of these various factors to the amyloid pathway has not been overlooked in most instances. Several lines of evidence suggest that G protein-coupled receptors (GPCRs) play an important role in cellular signaling. Indeed, manipulation of transmembrane signaling by GPCRs is one of the most important therapeutic targets although, it has not been fully exploited in AD and other neurodegenerative diseases. Maudsley and colleagues (page 3-19) present a timely review on the complexity of G proteincoupled receptor signaling in neuronal tissue and its implications for novel therapeutics. The authors note that, with better understanding of the complexity of GPCR signaling, the rational design of ligands possessing increased specific efficacy and attenuated side effects should become the norm for drug development using this important and ubiquitous target. In the context of signaling, Aghdam and Barger discuss (page 21-31) the potential for therapeutic use of lithium in neuroprotective strategies and further elaborate both the hopes and caveats of this strategy.....

The manipulation of transmembrane signaling by G protein-coupled receptors (GPCRs) constitutes perhaps the single most important therapeutic target in medicine. Therapeutics acting on GPCRs have traditionally been classified as agonists, partial agonists, or antagonists based on a two state model of receptor function embodied in the ternary complex model. Over the past decade, however, many lines of investigation have shown that GPCR signaling exhibits greater diversity and ‘texture’ than previously appreciated. Signal diversity arises from numerous factors, among them the ability of receptors to adopt multiple ‘active’ states with different effector coupling profiles, the formation of receptor dimers that exhibit unique pharmacology, signaling, and trafficking, the dissociation of receptor ‘activation’ from desensitization and internalization, and the discovery that non-G protein effectors mediate some aspects of GPCR signaling. At the same time, clustering of GPCRs with their downstream effectors in membrane microdomains, and interactions between receptors and a plethora of multidomain scaffolding proteins and accessory/chaperone molecules confers signal preorganization, efficiency, and specificity. More importantly it is likely that alteration in the interactions of these proteins with GPCRs may occur in aging or neurodegenerative disorders, thus defining a distinct ‘pharmacology’ from that seen in young organisms or normal physiology. In this context, the concept of agonist selective trafficking of receptor signaling, which recognizes that a bound ligand may select between a menu of ‘active’ receptor conformations and induce only a subset of the possible response profile, presents the opportunity to develop drugs that change the quality as well as the quantity of efficacy and enhance these qualities for specific disorders or other paradigms. As a more comprehensive understanding of the complexity of GPCR signaling is developed, the rational design of ligands possessing increased specific efficacy and attenuated side effects may become the standard mode of drug development.

For over fifty years lithium has been a fundamental component of therapy for patients with bipolar disorders. Lithium has been considered recently for its potential to alleviate neuronal loss and other neurodegeneration processes. For instance, lithium reduces the severity of some behavioral complications of Alzheimer's disease (AD). And there are growing indications that lithium may be of benefit to the underlying pathology of AD, as well as an array of other common CNS disorders, including stroke, Parkinson's disease, and Huntington's disease. Despite these demonstrated and prospective therapeutic benefits, lithium's mechanism of action remains elusive, and opinions differ regarding the most relevant molecular targets. Lithium inhibits several enzymes; significant among these are inositol monophosphatase (IMPase), glycogen synthase kinase-3 (GSK-3), and the proteasome. Most recent publications discussing the medical application of lithium have converged on GSK-3, so this article reviews data and discussions regarding the roles and interactions of GSK-3 with other proteins and its proposed role in the pathogenesis of Alzheimer's disease.

There is evidence to suggest that testosterone loss constitutes a risk for cognitive decline and possibly dementia, and that elderly men might benefit from exogenous supplementation of testosterone. Studies in non-human animals repeatedly report neuroexcitatory and neuroprotective properties of testosterone and enhanced memory performance after acute or chronic treatment. Positive effects of testosterone supplementation in older men have been reported in several, but not all, studies and require replication in larger randomized clinical trials before recommendations for clinical practice can be made. The current review summarizes recent studies on the neurobiological connection between testosterone and cognitive function in humans and non-human animals. When appropriate, we use the hippocampus as a model structure given it's involvement in sexually dymorphic spatial ability and sensitivity to both androgens and aging. In addition, a number of potential explanations of the discrepancy between data obtained in humans and non-human animals are discussed.

The pineal and retinal melatonin regulates endogenous circadian rhythms, and has various physiological functions including neuromodulatory and vasoactive actions, antioxidative and neuroprotective properties. We have previously demonstrated that the melatonin 1a-receptor (MT1) is localized in human retinal cells and that the expression of MT1 is increased in Alzheimer’s disease (AD) patients. We now present the first immunohistochemical evidence for the cellular distribution of the second melatonin receptor, MT2, in the human retina and in AD patients. In elderly controls, MT2 was localized to ganglion and bipolar cells in the inner nuclear layer, and to the inner segments of the photoreceptor cells. In addition, cellular processes in inner and outer plexiform layers were strongly positive for MT2. In AD patients the overall intensity of MT2-staining was distinctly decreased in all observed cellular localizations. Our results indicate that MT2 in the humans, similar to MT1, may indeed be involved in transmitting melatonin’s effects in the retina, and AD pathology may impair MT2 expression. Since our previous results showed an increase in MT1 expression in AD retina, the two melatonin receptor subtypes appear to be differentially affected by the course of the neurodegenerative disorder.

Abnormalities in the intricate intracellular signalling pathways play a key role in the deregulation of either spontaneous (normal or pathological) or induced (therapeutic) cell death mechanisms. Some of these pathways are increasingly becoming molecular therapeutic targets in different processes, ranging from neurodegenerative diseases to cancer. Recent discoveries in research and treatment have shown that failure to induce selective cell apoptosis in hyperproliferative processes, like neoplastic diseases, and the failure to prevent spontaneous cell death in neurodegenerative diseases (HNDDs) such as Alzheimer's disease (AD), multiple sclerosis (MS), amyothrophic lateral sclerosis (ALS), Huntington's disease (HD), and retinitis pigmentosa (RP), can be interpreted as problems stemming from the same basic mechanisms but moving in diametrically opposed directions. The integrated approach advanced here represents an interdisciplinary attempt to stimulate an integrated vision of two otherwise widely separated areas of research, experimental neurology and oncology. This kind of approach to the prevention of apoptosis (therapeutic antiapoptosis) and/or other forms of cell death in HNNDs, as well as to resistance to therapeutic apoptosis in cancer (pathological antiapoptosis), has the scope to improve the understanding of the dualistic nature of the basic abnormalities underlying the pathological deregulation of cell death. In this context, an intracellular pH (pHi)-related approach to these opposed situations is advanced to provide a unified theory of the apoptosis-antiapoptosis machinery. Some potential therapeutic possibilities opened by these lines of research, regarding the utilization of human growth factors and/or cellular anti-acidification measures directed to sustain cellular acid-base homeostasis in different HNNDs are considered because of their potential therapeutic benefit. Finally, we advance some possible dangers and side-effects raised by these very same treatment efforts.

Osteopontin (OPN) is a glycophosphoprotein expressed by several cell types and has pro-adhesive, chemotactic, and cytokine-like properties. OPN is involved in a number of physiologic and pathologic events including angiogenesis, apoptosis, inflammation, oxidative stress, remyelination, wound healing, bone remodeling, cell migration and tumorigenesis. Since these functions of OPN, and the events that it regulates, are involved with neurodegeneration, we examined whether OPN was differentially expressed in the hippocampus of the Alzheimer's disease (AD) compared with agematched (59-93 years) control brain. We report for the first time the immunocytochemical localization of OPN in the cytoplasm of pyramidal neurons. In AD brains, there was a significant 41 % increase in the expression of neuron OPN compared with age-matched control brain. No staining of other neuronal cell types was observed. Additionally, there was a significant positive correlation between OPN staining intensity and both amyloid-β load (r2 = 0.25; P < 0.05; n = 20) and aging (r2 = 0.32; P < 0.01; n = 20) among all control and AD subjects. Controlling for age indicated that OPN expression was significantly influenced by amyloid-β load, but not age. While the functional consequences of this amyloid-β associated increase in OPN expression are unclear, it is notable that OPN is primarily localized to those neurons that are known to be vulnerable to AD-related neurite loss, degeneration and death. Given that the induction of OPN expression (and amyloid-β generation) is associated with remodeling and tumorigenesis, our results suggest that OPN may play a role in the aberrant re-entry of neurons into the cell cycle and/or neuronal remyelination in AD.

A large number of studies has firmly established that increases in oxidative damage occurs in Alzheimer's disease (AD). Such studies have demonstrated that increased in oxidative damage selectively occurs within the brain regions involved in regulating cognitive performance. Studies from our laboratory and others have provided experimental evidence that increased levels of oxidative damage occur in subjects with Mild Cognitive Impairment (MCI), which is believed to be one of the earliest stages of AD, and is a condition which is devoid of dementia or the extensive neurofibrillary pathology and neuritic plaque deposition observed in AD. Together, these data support a role for the accrual of oxidative damage potentially serving as an early event that then initiates the development of cognitive disturbances and pathological features observed in AD. Recent studies from our laboratory have demonstrated that a decline in protein synthesis capabilities occurs in the same brain regions which exhibit increased levels of oxidative damage in MCI and AD subjects. The focus of this review is to describe the large number of studies which suggest protein synthesis may be one of the earliest cellular processes disrupted by oxidative damage in AD. Taken together, these findings have important implications for understanding the molecular and cellular basis of AD, understanding the basis for oxidative stress in AD, and may have important implications for studies involving proteomics and proteolysis in AD.

In this 10-week, double-blind, fixed-dose study, elderly institutionalized patients with dementia and agitation were randomized (3:3:2) to quetiapine 200mg/day, 100mg/day, or placebo. The primary endpoint was change in Positive and Negative Syndrome Scale (PANSS)-Excitement Component (EC) scores at endpoint, analysed using last observation carried forward (LOCF) and observed cases (OC) approaches. Other efficacy measures were the Clinical Global Impression of Change (CGI-C), and response rates (percentage with ≥40% reduction [PANSS-EC]; “much” or “very much improved” [CGI-C]), Neuropsychiatric Inventory-Nursing Home version (NPI-NH), and Cohen-Mansfield Agitation Inventory (CMAI). The key safety measure was incidence of adverse events; change in Mini-Mental State Examination (MMSE) was also assessed. Baseline characteristics of 333 participants (quetiapine 200mg/day, n=117; quetiapine 100mg/day, n=124; placebo, n=92) and completion rates (63-65%) were comparable among groups. Compared with placebo, quetiapine 200mg/day was associated with clinically greater improvements in PANSS-EC (LOCF, p=0.065; OC, p=0.014 [ANCOVA]), CGI-C (LOCF, p=0.017; OC, p=0.002 [ANOVA]), and CGI-C response rates (LOCF, p=0.002; OC, p<0.001 [Chi-square test]). Quetiapine 100mg/day did not differentiate from placebo on these measures. There were no between-group differences in NPI-NH or CMAI. Incidences of cerebrovascular adverse events, postural hypotension, and falls were similar among groups. MMSE did not change in any group. Mortality was numerically higher in the quetiapine groups; rates were not statistically different from placebo. The results of this study suggest that quetiapine 200mg/day was effective and well-tolerated for treating agitation associated with dementia. However, caution should be exercised given the concerns regarding increased mortality with atypical antipsychotics in this vulnerable patient population.