Current Alzheimer Research

ISSN: 1567-2050

OPEN ACCESS ARTICLES

Contents


Induction of RhoGAP and Pathological Changes Characteristic of Alzheimer’s Disease by UAHFEMF Discharge in Rat Brain, 2005, 2, 559-569
Ing-Feng Chang and Huo-Yen Hsiao
[Abstract] [Full Text Article]


De Novo and Molecular Target-Independent Discovery of Orally Bioavailable Lead Compounds for Neurological Disorders, 2006, 3, 205-214
Laura K. Wing, Heather A. Behanna, Linda J. Van Eldik, D. Martin Watterson and Hantamalala Ralay Ranaivo
[Abstract] [Full Text Article]


A New Glucocorticoid Hypothesis of Brain Aging: Implications for Alzheimer’s Disease, 2007, 4, 205-212
Philip W. Landfield, Eric M. Blalock, Kuey-Chu Chen and Nada M. Porter
[Abstract] [Full Text Article]


Assembly of the Asparagine- and Glutamine-Rich Yeast Prions into Protein Fibrils, 2008, 5, 251-259
Luc Bousset, Jimmy Savistchenko and Ronald Melki
[Abstract] [Full Text Article]


Alzheimer’s Disease Drug Development in 2008 and Beyond: Problems and Opportunities, 2008, 5, 346-357
Robert E. Becker and Nigel H. Greig
[Abstract] [Full Text Article]



Abstracts


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Induction of RhoGAP and Pathological Changes Characteristic of Alzheimer’s Disease by UAHFEMF Discharge in Rat Brain
Ing-Feng Chang and Huo-Yen Hsiao

[Full Text Article]

Novel experiments with Ultrasound Associated with High Frequency Electromagnetic Field (UAHFEMF) irradiation on rats and mice found evidences of characteristic Alzheimer’s disease (AD) degenerations including neurite plaques, beta-amyloid, TAU plaque and deposition in cells, Neuro-Fibrillary Tangle and Paired Helical Filament (PHF) with rats and mice irradiated up to 2454 hours. Concomitant passive avoidance test was performed on six mice, and all showed signs of visual and auditory agnosia and lost cognition of threatening condition. The post section Thioflavin-S fluorescent microscopy found dilated ventricles and dense amyloid-deposition in Ca3 and dentate gyrus. In addition, PHF was identified in the 2454 hours-irradiated rat brain by electron microscope. A human T-cell activation RhoGTPase-activating protein (TAGAP) isoform b homolog (GenBank accession # P84107) induced in the UAHFEMF-treated rat brain was identified using electron spray ionization (ESI) liquid chromatography tandem mass spectrometry (LC/MS/MS). We hypothesized that one of the causes of AD can be the UAHFEMF discharges in human brain.


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De Novo and Molecular Target-Independent Discovery of Orally Bioavailable Lead Compounds for Neurological Disorders
Laura K. Wing, Heather A. Behanna, Linda J. Van Eldik, D. Martin Watterson and Hantamalala Ralay Ranaivo

[Full Text Article]

There is immediate potential to enhance success and innovation in drug development by pairing newly emerging approaches in medicinal chemistry and computational biology with knowledge gained from the recent era of high throughput screens and the early years of modern drug discovery when in vivo efficacy was an early “Go/No Go” project management decision. Focused, in-parallel synthetic chemistry platforms, combined with computational analyses serving as decision aids in planning, minimize the total number of compounds synthesized while maximizing the probability of creating bioavailable compounds that sample diverse chemical space. Incorporating a hierarchal strategy that emphasizes early selection of synthesized compounds based on biological or biophysical endpoints presents fewer and more relevant compounds for secondary evaluation of in vivo efficacy using animal screens with disease relevant or clinically translatable endpoints. We summarize here an interdisciplinary approach at the chemistry-biology interface that is used for the rapid discovery of novel lead compounds for neurodegenerative disorders, such as Alzheimer’s disease (AD). The chemistry platform uses established chemistries amenable to in-parallel strategies to create synthetic diversifications of the privileged pyridazine chemotype that sample a restricted chemical space. The hierarchal biology platform uses primary screens for in vitro activity and selectivity with the target cell type, and rapid secondary screens for in vivo efficacy and toxicity in animal models with good phenotypic penetrance for disease relevant pathophysiological endpoints or clinically translatable surrogate endpoints. For the AD case study, novel lead compounds were developed in less than two years by a small academic group, and corporate sponsored clinical trials are planned.


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A New Glucocorticoid Hypothesis of Brain Aging: Implications for Alzheimer’s Disease
Philip W. Landfield, Eric M. Blalock, Kuey-Chu Chen and Nada M. Porter

[Full Text Article]

The original glucocorticoid (GC) hypothesis of brain aging and Alzheimer’s disease proposed that chronic exposure to GCs promotes hippocampal aging and AD. This proposition arose from a study correlating increasing plasma corticosterone with hippocampal astrocyte reactivity in aging rats. Numerous subsequent studies have found evidence consistent with this hypothesis, in animal models and in humans. However, several results emerged that were inconsistent with the hypothesis, highlighting the need for a more definitive test with a broader panel of biomarkers. We used microarray analyses to identify a panel of hippocampal gene expression changes that were aging-dependent, and also corticoster-one-dependent. These data enabled us to test a key prediction of the GC hypothesis, namely, that the expression of most target biomarkers of brain aging should be regulated in the same direction (increased or decreased) by both GCs and aging. This prediction was decisively contradicted, as a majority of biomarker genes were regulated in opposite directions by aging and GCs, particularly inflammatory and astrocyte-specific genes. Thus, the initial hypothesis of simple positive co-operativity between GCs and aging must be rejected. Instead, our microarray data suggest that in the brain GCs and aging interact in more complex ways that depend on the cell type. Therefore, we propose a new version of the GC-brain aging hypothesis; its main premise is that aging selectively increases GC efficacy in some cell types (e.g., neurons), enhancing catabolic processes, whereas aging selectively decreases GC efficacy in other cell types (e.g., astrocytes), weakening GC anti-inflammatory activity. We also propose that changes in GC efficacy might be mediated in part by cell type specific shifts in the antagonistic balance between GC and insulin actions, which may be of relevance for Alzheimer’s disease pathogenesis.


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Assembly of the Asparagine- and Glutamine-Rich Yeast Prions into Protein Fibrils
Luc Bousset, Jimmy Savistchenko and Ronald Melki

[Full Text Article]

The proteins Ure2, Sup35 and Rnq1 from the baker’s yeast have infectious properties, termed prions, at the origin of heritable and transmissible phenotypic changes. It is widely believed that prion properties arise from the assembly of Ure2p, Sup35p and Rnq1p into insoluble fibrils.

Yeast prions possess regions crucial for their propagation that can be either N- or C-terminal. These regions have unusual amino acid composition. They are very rich in glutamine and asparagine residues and resemble in that to huntingtin, a protein involved in the neurodegenerative Huntington’s disease.

Yeast prions assembly process has been hypothesized to be the consequence of the properties of glutamines and asparagines to engage in polar protein-protein interactions, termed polar-zippers. While this can certainly occur under certain conditions, glutamine and asparagine residues can establish other kinds of interactions with a variety of amino acid residues thus mediating protein-protein interactions involved in the assembly of polypeptide chains into high molecular weight oligomers.

This review details the interactions that can be established by glutamine and asparagine residues that may allow a better understanding of their role in mediating protein-protein interactions and prion propagation.


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Alzheimer’s Disease Drug Development in 2008 and Beyond: Problems and Opportunities
Robert E. Becker and Nigel H. Greig

[Full Text Article]

Recently, a number of Alzheimer’s disease (AD) multi-center clinical trials (CT) have failed to provide statistically significant evidence of drug efficacy. To test for possible design or execution flaws we analyzed in detail CTs for two failed drugs that were strongly supported by preclinical evidence and by proven CT AD efficacy for other drugs in their class. Studies of the failed commercial trials suggest that methodological flaws may contribute to the failures and that these flaws lurk within current drug development practices ready to impact other AD drug development [1]. To identify and counter risks we considered the relevance to AD drug development of the following factors: (1) effective dosing of the drug product, (2) reliable evaluations of research subjects, (3) effective implementation of quality controls over data at research sites, (4) resources for practitioners to effectively use CT results in patient care, (5) effective disease modeling, (6) effective research designs.

New drugs currently under development for AD address a variety of specific mechanistic targets. Mechanistic targets provide AD drug development opportunities to escape from many of the factors that currently undermine AD clinical pharmacology, especially the problems of inaccuracy and imprecision associated with using rated outcomes. In this paper we conclude that many of the current problems encountered in AD drug development can be avoided by changing practices. Current problems with human errors in clinical trials make it difficult to differentiate drugs that fail to evidence efficacy from apparent failures due to Type II errors. This uncertainty and the lack of publication of negative data impede researchers’ abilities to improve methodologies in clinical pharmacology and to develop a sound body of knowledge about drug actions. We consider the identification of molecular targets as offering further opportunities for overcoming current failures in drug development.