Announcing AAPS and FDA Agreement to Build Quantitative Alzheimer's Disease Model

American Association of Pharmaceutical Scientists (AAPS) and Pharmacometrics, Office of Clinical Pharmacology, Food and Drug Administration (FDA) have a Cooperative Research and Development Agreement (CRADA) to build a quantitative Alzheimer’s Disease Model. AAPS is seeking fellows who are interested in applying quantitative ‘learning’ approaches for solving drug development and regulatory challenges. Specifically, the incumbent will work with the FDA Pharmacometrics group (Silver Spring, MD, USA) to develop and apply Alzheimer’s Disease Model to drug development. The fellowship is for 2 years. Requirements include an earned Pharm.D., Ph.D., M.D. or other professional doctorate related to pharmaceutical sciences or statistics. Clinical and pharmaceutical scientists with a good knowledge of pharmacokinetic and pharmacodynamic principles, an experience in mixed effects modeling including software skills (SAS, Splus, NONMEM, etc) or a statistician with a good knowledge of trial design and analyses principles with an interest in advanced innovative methods to explore clinical trial data are eligible for this fellowship. Proficiency with standard software (NONMEM, SAS or SPlus/R) is a must. This fellowship could also be a good opportunity for academicians who are willing to take 2 years of sabbatical leave. Good communication and writing skills are critical. Opportunities to learn and contribute in a dynamic team, to gain first-hand experience with regulatory aspects of Pharmacometrics, and to conduct and publish research in related areas are abundant. Candidates will need to be US permanent residents or citizens. Please forward your resume to: AAPS Attention: CRADA—Alzheimer’s Disease Model 2107 Wilson Boulevard, Suite 700 Arlington, VA 22201 crada@aaps.org http://www.aapspharmaceutica.com/crada Deadline for submissions: June 30, 2008

American Association of Pharmaceutical Scientists (AAPS) and Pharmacometrics, Office of Clinical Pharmacology, Food and Drug Administration (FDA) have a Cooperative Research and Development Agreement (CRADA) to build a quantitative Alzheimer’s Disease Model. AAPS is seeking fellows who are interested in applying quantitative ‘learning’ approaches for solving drug development and regulatory challenges. Specifically, the incumbent will work with the FDA Pharmacometrics group (Silver Spring, MD, USA) to develop and apply Alzheimer’s Disease Model to drug development. The fellowship is for 2 years. Requirements include an earned Pharm.D., Ph.D., M.D. or other professional doctorate related to pharmaceutical sciences or statistics. Clinical and pharmaceutical scientists with a good knowledge of pharmacokinetic and pharmacodynamic principles, an experience in mixed effects modeling including software skills (SAS, Splus, NONMEM, etc) or a statistician with a good knowledge of trial design and analyses principles with an interest in advanced innovative methods to explore clinical trial data are eligible for this fellowship. Proficiency with standard software (NONMEM, SAS or SPlus/R) is a must. This fellowship could also be a good opportunity for academicians who are willing to take 2 years of sabbatical leave. Good communication and writing skills are critical. Opportunities to learn and contribute in a dynamic team, to gain first-hand experience with regulatory aspects of Pharmacometrics, and to conduct and publish research in related areas are abundant. Candidates will need to be US permanent residents or citizens. Please forward your resume to: AAPS Attention: CRADA—Alzheimer’s Disease Model 2107 Wilson Boulevard, Suite 700 Arlington, VA 22201 crada@aaps.org www.aapspharmaceutica.com/crada Deadline for submissions: June 30, 2008

The American Association of Pharmaceutical Scientists (AAPS) covers the full range of areas of expertise associated with the resolution of concerns pertaining to drugs and drug products. This editorial highlights the initiatives, issues, and challenges that are the forefront of the pharmaceutical sciences in 2007. It also provides an overview of how these difficult questions are being addressed through the programs and events associated with the AAPS 2007 Annual Meeting that will be held at the San Diego, California, Convention Center from November 11 to 15, 2007.

This article examines 582 cooperative research and development agreements (CRDAs) between federal (Air Force) agencies and other partners. Those CRDAs that exchange technology in novel phases of development tend to be long in duration relative to agreements that share mature technology. While novel projects could just take longer to complete, the findings also suggest that holdup risks increase in novelty. The geographic proximity of partners also affects CRDA duration positively, which is consistent with higher levels of tacit technology exchange. Repeat CRDAs tend to be shorter in duration, which is evidence of reputation effects. Duration of CRDAs decreases over time, which supports the argument that organizational form familiarity reduces the risks of negotiating agreements. In addition, CRDAs complement other modes of governance and methods to finance innovation. Cooperative research and development agreements with for‐profit partners are nearly 50 percent shorter than those with nonprofit p...

Researchers at the Department of Energy (DOE) facilities at Oak Ridge perform a variety of basic and applied research involving lasers and laser technology. One of the major strengths at Oak Ridge is the combination of core capabilities in optical materials, optical diagnostics, and sensors. Communities benefiting from these core capabilities include environmental, biomedical, and industrial sponsors. Industry can interact with Oak Ridge in a variety of ways; with Cooperative Research and Development Agreements (CRADAs), through Work for Others (WFO) programs, and as User Center participants. Oak Ridge is also active in sponsoring workshops and symposia for industrial participants like the recently held (December 1993) “Optical Diagnostics in Manufacturing and Process Control” symposium. In this paper, an overview of a selection of laser technologies residing at Oak Ridge is provided. Examples of the application of these technologies are given as well as overviews of several on-going CRADAs with industrial partners.

HDAC3 inhibition has been shown to improve memory and reduce amyloid-β (Aβ) in Alzheimer's disease (AD) models, but the underlying mechanisms are unclear. We investigated the molecular effects of HDAC3 inhibition on AD pathology, using invitro and exvivo models of AD, based on our finding that HDAC3 expression is increased in AD brains. For this purpose, N2a mouse neuroblastoma cells as well as organotypic brain cultures (OBCSs) of 5XFAD and wild-type mice were incubated with various concentrations of the HDAC3 selective inhibitor RGFP966 (0.1-10 μM) for 24 h. Treatment with RGFP966 or HDAC3 knockdown in N2a cells was associated with an increase on amyloid precursor protein (APP) and mRNA expressions, without alterations in Aβ42 secretion. Invitro chromatin immunoprecipitation analysis revealed enriched HDAC3 binding at APP promoter regions. The increase in APP expression was also detected in OBCSs from 5XFAD mice incubated with 1 μM RGFP966, without changes in Aβ. In addition, HDAC3 inhibition resulted in a reduction of activated Iba-1-positive microglia and astrocytes in 5XFAD slices, which was not observed in OBCSs from wild-type mice. mRNA sequencing analysis revealed that HDAC3 inhibition modulated neuronal regenerative pathways related to neurogenesis, differentiation, axonogenesis, and dendritic spine density in OBCSs. Our findings highlight the complexity and diversity of the effects of HDAC3 inhibition on AD models and suggest that HDAC3 may have multiple roles in the regulation of APP expression and processing, as well as in the modulation of neuroinflammatory and neuroprotective genes.

A risk-based analysis of the AAPS conference report on quantitative bioanalytical methods validation and implementation

Since the late 1980s, the Cooperative Research and Development Agreement (CRADA) has been a prominent vehicle used to support collaboration between US federal laboratories and private firms. This paper examines the structure and goals of one of the most ambitious CRADAs conducted to date, the EUV CRADA, which involves three Department of Energy laboratories and leading US firms in the semiconductor industry and is aimed at the development of next-generation lithographic technologies. This large project is an important case study in ‘post-Cold-War’ technology policy and government-industry collaboration. Although the EUV project represents significant improvements in the design and management of CRADAs, it also illustrates the inherent difficulties of balancing political and economic goals in complex technology development programs.

Neurogenesis involves generation of new neurons through finely tuned multistep processes, such as neural stem cell (NSC) proliferation, migration, differentiation, and integration into existing neuronal circuitry in the dentate gyrus of the hippocampus and subventricular zone. Adult hippocampal neurogenesis is involved in cognitive functions and altered in various neurodegenerative disorders, including Alzheimer disease (AD). Ethosuximide (ETH), an anticonvulsant drug is used for the treatment of epileptic seizures. However, the effects of ETH on adult hippocampal neurogenesis and the underlying cellular and molecular mechanism(s) are yet unexplored. Herein, we studied the effects of ETH on rat multipotent NSC proliferation and neuronal differentiation and adult hippocampal neurogenesis in an amyloid β (Aβ) toxin-induced rat model of AD-like phenotypes. ETH potently induced NSC proliferation and neuronal differentiation in the hippocampus-derived NSC in vitro. ETH enhanced NSC proliferation and neuronal differentiation and reduced Aβ toxin-mediated toxicity and neurodegeneration, leading to behavioral recovery in the rat AD model. ETH inhibited Aβ-mediated suppression of neurogenic and Akt/Wnt/β-catenin pathway gene expression in the hippocampus. ETH activated the PI3K·Akt and Wnt·β-catenin transduction pathways that are known to be involved in the regulation of neurogenesis. Inhibition of the PI3K·Akt and Wnt·β-catenin pathways effectively blocked the mitogenic and neurogenic effects of ETH. In silico molecular target prediction docking studies suggest that ETH interacts with Akt, Dkk-1, and GSK-3β. Our findings suggest that ETH stimulates NSC proliferation and differentiation in vitro and adult hippocampal neurogenesis via the PI3K·Akt and Wnt·β-catenin signaling.

While the greatest risk factor for Alzheimer's disease (AD) is aging, women are disproportionately affected by the disease. Interestingly, the hippocampus and cerebellum exhibit gender-specific cytoarchitecture differences, which are associated with AD, despite the absence of a role in animal reproductive behavior or hormonal signaling. This study investigates the potential association of sex differences associated with AD by interrogating cerebellar and hippocampal volume in preclinical (MCI) as well as clinical phases of AD compared to cognitively normal patients (CN) and in an animal model of AD, the streptozotocin (STZ)-induced sporadic AD model. In order to investigate putative changes in cerebellum and hippocampus in a rat model of AD, we used a STZ-induced sporadic AD model at three different time points (2, 4, and 8 weeks) after surgery in male and female rats. Previous studies have reported hippocampal-dependent changes as well as sex-dependent behavioral and signaling effects in the STZ animal model of sporadic AD while our current study showed involvement of cerebellum-mediated changes. To interrogate the role of cerebellar volume in AD progression within the human context, we analyzed data available through the Alzheimer's Disease Neuroimaging Initiative (ADNI). In a cross-sectional analysis, we observed that levels of peripheral Glial Acidic Fibrillary Protein (GFAP) (astrocytic protein) were associated negatively with cerebellar and hippocampal volumes (β = -0.002, p-value = 0.04; β = -6.721, p-value < 0.0001) and were associated with sex specific differences in males. Our analysis identified that the effect on hippocampal volume was earlier in disease stage, reinforcing the relevance of longitudinal alterations of cerebellum and hippocampus volume over time. The STZ animal model of sporadic AD, corroborated the progressive changes in hippocampal volume and more minor and temporally delayed involvement of the cerebellum volume changes which were dependent on sex. This suggests that cerebellar involvement may be secondary to hippocampal neurodegeneration, and both regional differences were dependent on sex. Due to the association with GFAP, our findings may be due to network astrocyte connection spread regardless of primary pathology. Overall, our study uncovers a novel role for cerebellum in AD in a model and in the human context.

Editorial

Alzheimer's disease (AD), characterized by memory loss, cognitive decline, and dementia, is a progressive neurodegenerative disease. Although the long noncoding RNAs (lncRNAs) have recently been identified to play a role in the pathogenesis of AD, the specific effects of lncRNAs in AD remain unclear. In present study, we have investigated the expression profiles of lncRNAs in hippocampal of intranasal LPS-mediated Alzheimer's disease models in mice by microarray method. A total of 395 lncRNAs and 123 mRNAs was detected to express differently in AD models and controls (>2.0 folds, p<0.05). The microarray expression was validated by Quantitative Real-Time-PCR (qRT-PCR). The pathway analysis showed the mRNAs that correlated with lncRNAs were involved in inflammation, apoptosis, and nervous system related pathways. The lncRNA-TFs network analysis suggested the lncRNAs were mostly regulated by HMGA2, ONECUT2, FOXO1, and CDC5L. Additionally, lncRNA-target-TFs network analysis indicated the FOXL1, CDC5L, ONECUT2, and CDX1 to be the TFs most likely to regulate the production of these lncRNAs. This is the first study to investigate lncRNAs expression pattern in intranasal LPS-mediated Alzheimer's disease model in mice. And these results may facilitate the understanding of the pathogenesis of AD targeting lncRNAs.

Aim: In this study, we aimed to analyze the interactions between neuroplasticity-related proteins (DCX, EGR1, sFRP3) and metabolic markers (insulin, HbA1c, asprosin) in an STZ-induced Alzheimer's disease model, as well as to evaluate how changes in these parameters affect the pathophysiology of Alzheimer's disease (AD).Material and Methods: 14 male Wistar albino rats, aged 8 to 10 weeks, weighing 250–300 g, were used. The animals were divided into two groups: control and Alzheimer's model. The AD model was created by stereotaxic injection of STZ, and the control group was injected with artificial CSF. The animals were monitored for 14 days after surgery. At the end of the study, serum samples were collected and DCX, EGR1, sFRP3, insulin, gHbA1c, and asprosin levels were analyzed by ELISA. The variables were compared between the groups, and P-values &amp;lt; 0.05 were considered significant.Results: DCX and EGR1 levels showed borderline changes without statistical significance (p = 0.056 and p = 0.080, respectively), while sFRP3 levels were significantly higher in the AD group (p = 0.012). Insulin levels did not differ (p = 0.829), but asprosin and gHbA1c levels were significantly higher (p = 0.046 and p = 0.000, respectively), indicating metabolic derangement. Correlation analysis showed strong positive correlations between asprosin and gHbA1c (r = 0.807, p &amp;lt; 0.01) and sFRP3 and EGR1 (r = 0.780, p &amp;lt; 0.01), suggesting interconnected roles in AD pathophysiology.Conclusion: This study shows the relationship between neurogenesis and metabolic parameters in AD.

This Cooperative Research and Development Agreement (CRADA) has been a three-year collaboration among the Y-12 Plant Development Division, Blasch Precision Ceramics, Inc., and Surface Alloys, Inc. The purpose of the CRADA was to evaluate the production of a totally new crucible that would be noncarbon and that could perform like graphite. The effort required materials fabricated into a workable crucible. The goal was to produce a crucible that could be induction heated and allow melting of reactive metals without appreciable carbon contamination. The US Department of Energy programs involving casting uranium and its alloys have long been concerned with reducing deleterious carbon pickup that results from the use of graphite crucibles. Therefore, the results of this CRADA provide an alternative that can eliminate carbon pickup from the graphite crucible.

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.