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Vitamin E May Aid in Slowing down Alzheimer’s disease

A new study published in the January 1st online edition of the Journal of the American Medical Association discussed findings conducted at the Icahn School of Medicine at Mount Sinai. In this study, the school’s faculty worked with the Veterans Administration Medical Centers and found that alpha tocepherol, otherwise known as Vitamin E with antioxidants, could help slow functional decline of patients with mild-to-moderate Alzheimer’s disease. Problems of functional decline include issues with daily activities; shopping, preparing meals, planning, and traveling. This study could bring much welcomed aid from the estimated 5.4 million families and caregivers of 5.1 million patients suffering with mild to moderate Alzheimer’s disease.

Mary Sano, PhD, trial co-investigator, professor within the Icahn School of Medicine’s department of psychiatry, and director of research at the James J, Peters Veteran’s Administration Medical Center at the Bronx, New York headed up this study. She stated that since the days of cholesterase inhibitors, such as galantamine, donepezil, and rivastigmine, there were few options for patients with mild-to-moderate dementia. However, with the results of the current study run, the use of vitamin E could delay the progression of functional decline within mild-to-moderate Alzheimer’s disease patients by 19 percent per year, which would translate into 6.2 months benefit over the placebo. Vitamin E is nowadays easily purchasable and non-expensive, and it could be an effective treatment strategy for Alzheimer’s patients.

Team AD, the Veteran’s Administration Cooperative Randomized Trial of Vitamin E and mimantine in Alzheimer’s disease, examined the effects of vitamin E 2,000 IU/d, and 20 mg/d of memenatine, the placebo used. For the study, testing was conducted at 14 different Veteran’s Affairs Medical Centers, 613 patients with mild to moderate Alzheimer’s disease were followed from August 2007 until September 2012. Dr. Sano reported that in previous studies she conducted with moderately severe Alzheimer’s, vitamin E also slowed the disease’s progression.
1) Maurice W. Dysken, Mary Sano, Sanjay Asthana, Julia E. Vertrees, Muralidhar Pallaki, Maria Llorente, Susan Love, Gerard D. Schellenberg, J. Riley McCarten, Julie Malphurs, Susana Prieto, Peijun Chen, David J. Loreck, George Trapp, Rajbir S. Bakshi, Jacobo E. Mintzer, Judith L. Heidebrink, Ana Vidal-Cardona, Lillian M. Arroyo, Angel R. Cruz, Sally Zachariah, Neil W. Kowall, Mohit P. Chopra, Suzanne Craft, Stephen Thielke, Carolyn L. Turvey, Catherine Woodman, Kimberly A. Monnell, Kimberly Gordon, Julie Tomaska, Yoav Segal, Peter N. Peduzzi, Peter D. Guarino. Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease. JAMA, 2014; 311 (1): 33 DOI: 10.1001/jama.2013.282834
2) Mount Sinai Medical Center (2013, December 31). Vitamin E may delay decline in mild-to-moderate Alzheimer’s disease. ScienceDaily. Retrieved January 2, 2014, from¬ /releases/2013/12/131231163755.htm

By: Lauren Horne

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Eleven new Alzheimer's Risk Gense

A study by the International Genomics Project, published in Nature Genetics, identified eleven previously unknown genes that increase risk of developing Alzheimer’s. The research, which brought together leading Alzheimer’s researchers, was comprised of four teams from one hundred and forty-five global academic centers working toward the common goal of determining new information surrounding the genetics of Alzheimer’s disease.

One of the most significant findings of the study, which involved the genome data of 74,076 people from fifteen different countries, relates to the HLA-DRB5/DRB1 major histocompatibility complex region of the brain. The research shows that this same region, associated with multiple sclerosis and Parkinson’s, is involved somehow in Alzheimer’s disease.

The discovered genes revolved mostly around late onset Alzheimer’s, the most common type of the disease. Professor Julie Williams, head of neurodegeneration at Cardiff School of Medicine’s Medical Research Council, says that the teams can now shift their focus to early on-set Alzheimer’s, the most severe form that usually begins around ages 40-50. The Professor says that indentified genetic architecture may make finding new genes easier, and that the genes yield clues for scientists to seek out during research.

These eleven genes bring the total of indentified risk genes to twenty-one, and scientists hope that such findings will help improve knowledge about the mechanisms behind the neurodegenerative disease. The four groups used genome-wide association analysis work that previously identified the first ten risk genes. Professor Williams cautions that although twenty-one of these genes are now uncovered, a large section of genetic risk for Alzheimer’s remains unknown. Williams ends by saying that the identification of more risk genes is imperative to the continued research and development of these findings.

1) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease; Jean-Charles Lambert, Carla A Ibrahim-Verbaas, Denise Harold, Adam C Naj, Rebecca Sims, Céline Bellenguez, Gyungah Jun, Anita L DeStefano, et al.; Nature Genetics Published online 27 October 2013; DOI:10.1038/ng.2802.
2) Medical News Today (Published 10/28/13). Scientists Discover Eleven New Alzheimer’s Risk Genes. Retrieved 10/30/13 from

By Emma Henson

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ACE Inhibitors and Alzheimer’s Prevention

Cedars-Sinai scientists published a study in Journal of Clinical Investigation that suggests ACE inhibitors, in the right context and at the right time, can be a good thing.

Many people with high blood pressure take ACE inhibitors, medication meant to widen blood vessels by limiting activity of ACE (angiotensin-converting enzyme), a naturally occurring protein. However, in new research using a rodent model of Alzheimer's Disease, it is shown that genetically targeting certain immune blood cells to overproduce the ACE enzyme can systematically break down defective proteins in the brain associated with Alzheimer’s disease and cognitive decline. The results demonstrate that ACE, not known for central nervous system involvement, can actually induce a protective immune response in the brain to ultimately affect cognition. In addition, ACE could possibly have a novel role in the clearance of excessive beta-amyloid plaques from brain blood vessels.

Kenneth Bernstein, MD, designed a rodent model to study the effects of an over-expression of ACE in macrophages, microglia, and similar cells of the immune system. The study shows the value of a strategy that delivers an enzyme to attack and destroy beta-amyloid to eschew resultant inflammation. Scientists are yet to determine if the deposits result from overproduction of beta-amyloid or an inability of mechanisms, like the immune system, to clear the plaques. Either way, a common view supports any strategy that reduces the amount of beta-amyloid protein in the brain as a way to delay progression of Alzheimer's.

Ultimately, rodents in this model with Alzheimer’s-like symptoms and those engineered to over-express ACE in immune cells produced offspring with greatly reduced beta-amyloid protein levels, inflammation, and increased performance on learning and memory tests.

The research contemplates ACE as a natural enzyme that can be harmful or helpful, depending on how and where it is active. Though it contributes to angiotensin II production, a hormone that causes high blood pressure, it can also quickly and efficiently lead an immune system response to beta-amyloid protein.

1) Kenneth E. Bernstein, Yosef Koronyo, Brenda C. Salumbides, Julia Sheyn, Lindsey Pelissier, Dahabada H.J. Lopes, Kandarp H. Shah, Ellen A. Bernstein, Dieu-Trang Fuchs, Jeff J.-Y. Yu, Michael Pham, Keith L. Black, Xiao Z. Shen, Sebastien Fuchs, Maya Koronyo-Hamaoui. Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI66541
2) Cedars-Sinai Medical Center. (2014, February 3). Can a protein controlling blood pressure enhance immune responses and prevent Alzheimer's?. ScienceDaily. Retrieved February 6, 2014 from

Written by Emma Henson
Edited by Patrizio Murdocca

Genentech's Planned Clinical Trial for Alzheimer's Disease

In an international collaboration, Genentech of S. San Francisco, California, the Banner Alzheimer’s Institute in Phoenix, Arizona, and the US National Institutes of Health are joining to spend over $96 million for the first of three clinical trials for the drug crenezumab. Created by Genentech, this experimental drug is a humanized monoclonal antibody (mAb) that binds to the amyloid beta protein (Aβ). The main experimental group will be people who are likely to develop early Alzheimer’s disease due to autosomal dominant gene mutations. Other biomarkers will be looked at as well. These three clinical trials will determine the validity of the amyloid beta theory, and the tracking of biomarkers and clinical outcomes will allow future trials.

Despite the significant amount of risks, including the fact that the drug will be tested on healthy individuals with normal cognitive function, with the support of regulators from the United States and Europe, the researchers have been successful in gaining financial support from industry partners. Other funding comes from philanthropic groups and the government.

Crenezumab was chosen because it should be more effective in early disease. Not only does it target a variety of amyloid beta forms, but its mechanism differs from that of other anti-Aβ antibodies since it counts on microglial engulfment of Aβ.

The first trial, sponsored by the Alzheimer’s Prevention Initiative (API), will start either late 2012 or early 2013. The population the drug will be tested on is an extended family in Medellin, Colombia, of 300 members. Many are carriers of the gene encoding presenilin-1 (PS1), which onsets Alzheimer’s symptoms around 50 years of age. Some noncarrier controls and participants with varied mutations in the United States will participate in this trial as well. The duration of the trial will be five years and will include an interim analysis at two years to test the effects of crenezumab on a set of Alzheimer’s biomarkers. If there is any response from the biomarkers, the trial will continue with the hopes of improved cognitive function at the end. The second trial, sponsored by Dominated Inherited Alzheimer’s Network (DIAN) is a two-staged, five year trial on carriers of autosomal dominant mutations of PS1, PS2, and amyloid precursor protein (APP). The first stage will test three drugs that target the Aβ protein and will commence late 2012 or early 2013. The third and largest trial will start mid-2013. Known as the “Anti-Amyloid Treatment in Asymptomatic AD” (A4 trial), it is sponsored by Alzheimer’s Disease Cooperative Study and will include 1,000 participants from the general population in their 70s and early 80s. However, unlike the other two trials, these participants will be chosen based on measurements (by amyloid positive emission tomography) of high Aβ burdens in their brain. The duration will be three years of double-blind treatment with two years of follow-up. The goal of the last trial, as stated by neurologist Reisa Sperling, the head of the A4 trial, is “to see a difference in the slop of decline, in the rate of decline”.

Drugs that have targeted Aβ, such as Eli Lilly’s solanezumab, have failed their clinical trials. This may be a result of the overdue treatment, as the disease would have already damaged the neurons for too long for the drugs to be effective. Despite the risk involved, the upcoming trials for crenezumab mark a new approach towards treatment for Alzheimer’s disease.

Garber, Ken. "Genentech's Alzheimer's antibody trial to study disease prevention." Nature Biotechnology. 30.8 (2012): 731-32. Print.

Wendy Liu
August 17, 2012

Michael Mullan Alzheimer's Disease

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Anti-Tumoral Activity of a Short Decapeptide Fragment of the Alzheimer's Abeta Peptide.

The inhibition of angiogenesis is regarded as a promising avenue for cancer treatment. Although some antiangiogenic compounds are in the process of development and testing, these often prove ineffective in vivo, therefore the search for new inhibitors is critical. We have recently identified a ten amino acid fragment of the Alzheimer Abeta peptide that is anti-angiogenic both in vitro and in vivo. In the present study, we investigated the antitumoral potential of this decapeptide using human MCF-7 breast carcinoma xenografts nude mice. We observed that this decapeptide was able to suppress MCF-7 tumor growth more potently than the antiestrogen tamoxifen. Inhibition of tumor vascularization as determined by PECAM-1 immunostaining and decreased tumor cell proliferation as determined by Ki67 immunostaining were observed following treatment with the Abeta fragment. In vitro, this peptide had no direct impact on MCF-7 tumor cell proliferation and survival suggesting that the inhibition of tumor growth and tumor cell proliferation observed in vivo is related to the antiangiogenic activity of the peptide. Taken together these data suggest that this short Abeta derivative peptide may constitute a new antitumoral agent.

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Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia among the aging population and is characterized pathologically by the progressive intracerebral accumulation of beta-amyloid (Abeta) peptides and neurofibrillary tangles. The level of proangiogenic growth factors and inflammatory mediators with proangiogenic activity is known to be elevated in AD brains which has led to the supposition that the cerebrovasculature of AD patients is in a proangiogenic state. However, angiogenesis depends on the balance between proangiogenic and antiangiogenic factors and the brains of AD patients also show an accumulation of endostatin and Abeta peptides which have been shown to be antiangiogenic. To determine whether angiogenesis is compromised in the brains of two transgenic mouse models of AD overproducing Abeta peptides (Tg APPsw and Tg PS1/APPsw mice), we assessed the growth and vascularization of orthotopically implanted murine gliomas since they require a high degree of angiogenesis to sustain their growth. Our data reveal that intracranial tumor growth and angiogenesis is significantly reduced in Tg APPsw and Tg PS1/APPsw mice compared with their wild-type littermates. In addition, we show that Abeta inhibits the angiogenesis stimulated by glioma cells when cocultured with human brain microvascular cells on a Matrigel layer. Altogether our data suggest that the brain of transgenic mouse models of AD does not constitute a favorable environment to support neoangiogenesis and may explain why vascular insults synergistically precipitate the cognitive presentation of AD.

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Characterization and use of human brain microvascular endothelial cells to examine β-amyloid exchange in the blood-brain barrier. Bachmeier C, Mullan M, Paris D.

Alzheimer's disease (AD) is characterized by excessive cerebrovascular deposition of the β-amyloid peptide (Aβ). The investigation of Aβ transport across the blood-brain barrier (BBB) has been hindered by inherent limitations in the cellular systems currently used to model the BBB, such as insufficient barrier properties and poor reproducibility. In addition, many of the existing models are not of human or brain origin and are often arduous to establish and maintain. Thus, we characterized an in vitro model of the BBB employing human brain microvascular endothelial cells (HBMEC) and evaluated its utility to investigate Aβ exchange at the blood-brain interface. Our HBMEC model offers an ease of culture compared with primary isolated or coculture BBB models and is more representative of the human brain endothelium than many of the cell lines currently used to study the BBB. In our studies, the HBMEC model exhibited barrier properties comparable to existing BBB models as evidenced by the restricted permeability of a known paracellular marker. In addition, using a simple and rapid fluormetric assay, we showed that antagonism of key Aβ transport proteins significantly altered the bi-directional transcytosis of fluorescein-Aβ (1-42) across the HBMEC model. Moreover, the magnitude of these effects was consistent with reports in the literature using the same ligands in existing in vitro models of the BBB. These studies establish the HBMEC as a representative in vitro model of the BBB and offer a rapid fluorometric method of assessing Aβ exchange between the periphery and the brain.

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Depletion of CXCR2 inhibits γ-secretase activity and amyloid-β production in a murine model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to progressive cognitive decline. Recent studies from our group and others have suggested that certain G-protein coupled receptors (GPCRs) can influence the processing of the amyloid precursor protein (APP). Earlier, we demonstrated that stimulation of a chemokine receptor, CXCR2, results in enhanced γ-secretase activity and in increased amyloid-beta (Aβ) production. Taken together, results obtained from in vitro studies indicate that therapeutic targeting of CXCR2 might aid in lowering Aβ levels in the AD brain. To better understand the precise function and to predict the consequences of CXCR2 depletion in the AD brain, we have crossed CXCR2 knockout mice with mice expressing presenilin (PS1 M146L) and APPsw mutations (PSAPP). Our present study confirms that CXCR2 depletion results in reduction of Aβ with concurrent increases of γ-secretase substrates. At the mechanistic level, the effect of CXCR2 on γ-secretase was not found to occur via their direct interaction. Furthermore, we provide evidence that Aβ promotes endocytosis of CXCR2 via increasing levels of CXCR2 ligands. In conclusion, our current study confirms the regulatory role of CXCR2 in APP processing, and poses it as a potential target for developing novel therapeutics for intervention in AD.

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Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood-brain barrier.

Several large population-based or clinical trial studies have suggested that certain dihydropyridine (DHP) L-type calcium channel blockers (CCBs) used for the treatment of hypertension may confer protection against the development of Alzheimer disease (AD). However, other studies with drugs of the same class have shown no beneficial clinical effects. To determine whether certain DHPs are able to impact underlying disease processes in AD (specifically the accumulation of the Alzheimer Aβ peptide), we investigated the effect of several antihypertensive DHPs and non-DHP CCBs on Aβ production. Among the antihypertensive DHPs tested, a few, including nilvadipine, nitrendipine and amlodipine inhibited Aβ production in vitro, whereas others had no effect or raised Aβ levels. In vivo, nilvadipine and nitrendipine acutely reduced brain Aβ levels in a transgenic mouse model of AD (Tg PS1/APPsw) and improved Aβ clearance across the blood-brain barrier (BBB), whereas amlodipine and nifedipine were ineffective showing that the Aβ-lowering activity of the DHPs is independent of their antihypertensive activity. Chronic oral treatment with nilvadipine decreased Aβ burden in the brains of Tg APPsw (Tg2576) and Tg PS1/APPsw mice, and also improved learning abilities and spatial memory. Our data suggest that the clinical benefit conferred by certain antihypertensive DHPs against AD is unrelated to their antihypertensive activity, but rely on their ability to lower brain Aβ accumulation by affecting both Aβ production and Aβ clearance across the BBB.

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Induction of drug efflux protein expression by venlafaxine but not desvenlafaxine.

Venlafaxine and its metabolite desvenlafaxine are serotonin-norepinephrine reuptake inhibitors currently prescribed for the treatment of depression. Previously, it was reported that venlafaxine is an inducer of MDR1, the gene responsible for P-glycoprotein (P-gp). The present study expanded upon these findings by examining the effect of venlafaxine and desvenlafaxine on the expression of both P-gp and the breast cancer resistance protein (BCRP) in human brain endothelial cells (HBMEC), an in vitro model of the blood-brain barrier (BBB). The HBMEC were treated for 1 h with various concentrations (500 nM to 50 µM) of venlafaxine and desvenlafaxine. Western blot analysis revealed treatment with venlafaxine significantly induced the expression of P-gp (2-fold) and BCRP (1.75-fold) in a dose-dependent manner, while treatment with desvenlafaxine had no effect on drug efflux transporter expression. To determine the functional significance of this effect, the permeability of a known drug efflux probe, rhodamine 123, across the BBB model and Caco-2 cells, a model of intestinal absorption, were examined. Treatment with venlafaxine (1-50 µM) for 1 h significantly reduced the apical-to-basolateral permeability of R123 across the BBB model (30%) and Caco-2 cell monolayers (25%), indicative of increased drug efflux transporter expression at the apical membrane. Conversely, desvenlafaxine had no effect on R123 permeability in either cellular model. These studies indicate that venlafaxine, but not desvenlafaxine is an inducer of drug efflux transporter expression, which consequently increases the potential for clinical drug-drug interactions. Therefore, based on these preliminary results, caution should be taken when prescribing venlafaxine with other P-gp substrates.

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Selective dihydropyiridine compounds facilitate the clearance of β-amyloid across the blood-brain barrier.

Increasing evidence suggests that the soluble form of the β-amyloid peptide (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease. Previously, we reported that treatment with certain antihypertensive dihydropyridine (DHP) compounds can mitigate Aβ production in whole cells and reduce brain Aβ burden in a mouse model of Alzheimer's disease. As Aβ clearance across the blood-brain barrier (BBB) is a key regulatory step in the deposition of Aβ in the brain, we examined the effect of DHP treatment on Aβ brain clearance. Treatment with certain DHP compounds significantly increased Aβ(1-42) transcytosis across the BBB in an in vitro model. The rank order of these compounds was nitrendipine>nicardipine=cilnidipine=lercanidipine>nimodipine>azelnidipine=nilvadipine. Conversely, amlodipine, felodipine, isradipine, and nifedipine had no effect on Aβ(1-42) BBB transcytosis. In an in vivo paradigm of Aβ clearance across the BBB, peripheral administration of nitrendipine, cilnidipine, and nilvadipine to wild-type animals facilitated the brain clearance of centrally administered exogenous Aβ(1-42), whereas with amlodipine, there was no effect. We also observed improved cognitive function in mice treated with nilvadipine following central Aβ(1-42) insult. Thus, in addition to the effect of certain DHP compounds on Aβ production, we demonstrate that certain DHP compounds also facilitate the clearance of Aβ across the BBB. This dual mechanism of action may be particularly effective in attenuating Aβ brain burden in Alzheimer's disease and could open the door to a new class of therapies for the treatment of this disease.

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Feasibility of Predicting MCI/AD Using Neuropsychological Tests and Serum β-Amyloid.

We examined the usefulness of brief neuropsychological tests and serum Aβ as a predictive test for detecting MCI/AD in older adults. Serum Aβ levels were measured from 208 subjects who were cognitively normal at enrollment and blood draw. Twenty-eight of the subjects subsequently developed MCI (n = 18) or AD (n = 10) over the follow-up period. Baseline measures of global cognition, memory, language fluency, and serum Aβ(1-42) and the ratio of serum Aβ(1-42)/Aβ(1-40) were significant predictors for future MCI/AD using Cox regression with demographic variables, APOE ε4, vascular risk factors, and specific medication as covariates. An optimal sensitivity of 85.2% and specificity of 86.5% for predicting MCI/AD was achieved using ROC analyses. Brief neuropsychological tests and measurements of Aβ(1-42) obtained via blood warrants further study as a practical and cost effective method for wide-scale screening for identifying older adults who may be at-risk for pathological cognitive decline.

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Flavonoids lower Alzheimer's Aβ production via an NFκB dependent mechanism.

Alzheimer’s disease (AD) is characterized by the brain accumulation of Aβ peptides and by the presence of neurofibrillary tangles. Aβ is believed to play an important role in AD and it has been shown that certain flavonoids can affect Aβ production. Recently, it was suggested that the Aβ lowering properties of flavonoids are mediated by a direct inhibition the β-secretase (BACE-1) activity, the rate limiting enzyme responsible for the production of Aβ peptides. Westernblots and ELISAs were employed to monitor the impact of flavonoids on amyloid precursor protein processing and Aβ production. A cell free chemoluminescent assay using human recombinant BACE-1 was used to assess the effect of flavonoids on BACE-1 activity. The effect of flavonoids on NFκB activation was determined by using a stable NFκB luciferase reporter cell line. Molecular docking simulations were performed to predict the binding of flavonoids to the BACE-1 catalytic site. Real time quantitative PCR was used to determine the effect of flavonoids on BACE-1 transcription. We show in a cell free assay that flavonoids are only weak inhibitors of BACE-1 activity. Docking simulation studies with different BACE-1 structures also suggest that flavonoids are poor BACE-1 inhibitors as they appear to adopt various docking poses in the active site pocket and have weak docking scores that differ as a function of the BACE-1 structures studied. Moreover, a weak correlation was observed between the effect of flavonoids on Aβ production in vitro and their ability to lower BACE-1 activity suggesting that the Aβ lowering properties of flavonoids in whole cells are not mediated via direct inhibition of BACE-1 activity. We found however a strong correlation between the inhibition of NFκB activation by flavonoids and their Aβ lowering properties suggesting that flavonoids inhibit Aβ production in whole cells via NFκB related mechanisms. As NFκB has been shown to regulate BACE-1 expression, we show that NFκB lowering flavonoids inhibit BACE-1 transcription in human neuronal SH-SY5Y cells. Altogether, our data suggest that flavonoids inhibit Aβ and sAPPβ production by regulating BACE-1 expression and not by directly inhibiting BACE-1 activity.

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Identification of Plasma Biomarkers of TBI Outcome Using Proteomic Approaches in an APOE Mouse Model.

Abstract The current lack of diagnostic and prognostic biomarkers for traumatic brain injury (TBI) confounds treatment and management of patients and is of increasing concern as the TBI population grows. We have generated plasma proteomic profiles from mice receiving TBI by controlled cortical impact at either 1.3 mm or 1.8 mm depth, comparing these against those of sham injured-animals to identify plasma biomarkers specific to mild or severe TBI at 24 hours, 1 month, or 3 months post-injury. To identify possible prognostic biomarkers, we used apolipoprotein E (APOE)3 and APOE4 transgenic mice, which demonstrate relatively favorable and unfavorable outcomes respectively, following TBI. Using a quantitative proteomics approach (isobaric tagging for relative and absolute quantitation - iTRAQ) we have identified proteins that are significantly modulated as a function of TBI and also in response to the TBI*APOE genotype interaction, the latter representing potential prognostic biomarkers. These preliminary data clearly demonstrate plasma protein changes that are not only injury dependent but also interaction dependent. Importantly, these results demonstrate the presence of TBI-dependent and interaction-dependent plasma proteins at a 3-month time point, which is a considerable time post-injury in the mouse model, and will potentially be of significance for combat veterans receiving assessment at extended periods post-injury. Furthermore, our identification of clusters of functionally related proteins indicates disturbance of particular biological modules, which potentially increases their value beyond that of solitary biomarkers.

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Anatabine lowers Alzheimer's Aβ production in vitro and in vivo

Brain Aβ accumulation represents a key pathological hallmark in Alzheimer’s disease. In this study, we investigated the impact of anatabine, a minor alkaloid present in plants of the Solanacea family on Aβ production in vitro using a cell line overexpressing the human amyloid precursor protein (APP) and in vivo using a transgenic mouse model of Alzheimer’s disease. In vitro, anatabine lowers Aβ₁₋₄₀ and Aβ₁₋₄₂ levels in a dose dependent manner and reduces sAPPβ production without impacting sAPPα levels suggesting that anatabine lowers Aβ production by mainly impacting the β-cleavage of APP. Additionally, we show that anatabine lowers NFκB activation at doses that inhibit Aβ production in vitro. Since NFκB is known to regulate BACE-1 expression (the rate limiting enzyme responsible for Aβ production), we determined the impact of anatabine on BACE-1 transcription. We show that anatabine inhibits BACE-1 transcription and reduces BACE-1 protein levels in human neuronal like SHSY-5Y cells suggesting that the Aβ lowering properties of anatabine are mediated via a regulation of BACE-1 expression. In vivo, we show that an acute treatment with anatabine for four days significantly lowers brain soluble Aβ₁₋₄₀ and Aβ₁₋₄₂ levels in a transgenic mouse model of Alzheimer’s disease. Altogether our data suggest that anatabine may represent an interesting compound for regulating brain Aβ accumulation.

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Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease.

Expression levels of tumor necrosis factor (TNF) receptors, TNFR1 and TNFR2, are significantly changed in the brains and cerebrospinal fluid (CSF) with Alzheimer’s disease (AD). Moreover, we also found that, in an Alzheimer’s mouse model, genetic deletion of TNF receptor (TNFR1) reduces amyloid plaques and amyloid beta peptides (Aβ) production through β-secretase (BACE1) regulation. TNF-α converting enzyme (TACE/ADAM-17) does not only cleave pro- TNF-α but also TNF receptors, however, whether the TACE activity was changed in the CSF was not clear. In this study, we examined TACE in the CSF in 32 AD patients and 27 age-matched healthy controls (HCs). Interestingly, we found that TACE activity was significantly elevated in the CSF from AD patients compared with HCs. Furthermore, we also assayed the CSF levels of TACE cleaved soluble forms of TNFR1 and TNFR2 in the same patients. We found that AD patients had higher levels of both TACE cleaved soluble TNFR1 (sTNFR1) and TNFR2 (sTNFR2) in the CSF compared to age- and gender-matched healthy controls. Levels of sTNFR1 correlated strongly with the levels of sTNFR2 (rs = 0.567-0.663, p < 0.01). The levels of both sTNFR1 and sTNFR2 significantly correlated with the TACE activity (rs = 0.491-0.557, p < 0.05). To examine if changes in TACE activity and in levels of cleaved soluble TNFRs are an early event in the course of AD, we measured these molecules in the CSF from 47 subjects with mild cognitive impairment (MCI), which is considered as a preclinical stage of AD. Unexpectedly, we found significantly higher levels of TACE activity and soluble TNFRs in the MCI group than that in AD patients. These results suggest that TACE activity and soluble TNF receptors may be potential diagnostic candidate biomarkers in AD and MCI.

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Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons.

The distribution of postsynaptic glutamate receptors has been shown to be regulated by proimmunocytokine tumor necrosis factor α (TNF-α) signaling. The role of TNF-α receptor subtypes in mediating glutamate receptor expression, trafficking, and function still remains unclear. Here, we report that TNF receptor subtypes (TNFR1 and TNFR2) differentially modulate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) clustering and function in cultured cortical neurons. We find that genetic deletion of TNFR1 decreases surface expression and synaptic localization of the AMPAR GluA1 subunit, reduces the frequency of miniature excitatory postsynaptic current (mEPSC), and reduces AMPA-induced maximal whole-cell current. In addition, these results are not observed in TNFR2-deleted neurons. The decreased AMPAR expression and function in TNFR1-deleted cells are not significantly restored by short (2 h) or long (24 h) term exposure to TNF-α. In TNFR2-deleted cells, TNF-α promotes AMPAR trafficking to the synapse and increases mEPSC frequency. In the present study, we find no significant change in the GluN1 subunit of NMDAR clusters, location, and mEPSC. This includes applying or withholding the TNF-α treatment in both TNFR1- and TNFR2-deleted neurons. Our results indicate that TNF receptor subtype 1 but not 2 plays a critical role in modulating AMPAR clustering, suggesting that targeting TNFR1 gene might be a novel approach to preventing neuronal AMPAR-mediated excitotoxicity.-He, P., Liu, Q., Wu, J., Shen, Y. Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons.

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Institute targets in on Alzheimer's

May 7, 2007 - At St. James Hospital in Dublin, Ireland, a nurse is checking the blood pressure of a 62-year-old man. Later, a tech will use a hand-held scanner to measure blood flow in his middle cerebral artery.

The patient has never met Michael Mullan, nor Fiona Crawford. But some 4,150 miles away, they could hardly be happier about his test results.

They show that the man, whose identity is confidential, is showing no adverse reactions to a drug that might be a promising treatment for Alzheimer's disease.

That is good news for Mullan and Crawford. Directors of the Roskamp Institute, on Whitfield Avenue in southern Manatee County, they are running a clinical trial of Nilvadipine, a drug widely used abroad but not approved in the United States.

The drug is intended to lower blood pressure. But in studies on mice, Roskamp researchers found it also reduced the level of a protein in the brain believed to be at the heart of Alzheimer's.

The Ireland trial just completed its second phase, a safety study, and the 20 patients taking the drug showed almost no ill effects, paving the way for a broader study.

The clinical trial is the institute's highest-profile project, but its two dozen scientists also work in fields including drug addiction and head injury.

With even more promising treatments deep in its labs, the little nonprofit academic center is becoming more and more a biotechnology start-up.

Birth of the institute

The institute was born in 1997, but its origins date back another 40 years.

Bob Roskamp was a high school physics teacher. His older brother, diagnosed with schizophrenia, killed himself.

Roskamp tells the story with understatement: "Obviously, it catches your attention in a big way."

The loss of his brother prompted him to give up teaching and work on opening homes for developmentally disabled adults. He later moved into developing housing communities for seniors.

He began selling his companies -- including his Freedom Group to American Retirement Group for $23 million in cash and $14.9 million in stock -- leaving him with a question: "What do we do with these surplus dollars?"

The answer is in the logo of the institute bearing his name: "Curing Diseases of the Mind."

Roskamp and his wife, Diane, are among the pioneers of a style of philanthropy, now more widely followed, of carefully aiming resources at one target and tracking performance.

"Instead of spreading it thinly throughout the world, we would 'rifle-shot' it, and have a lot more fun with it," he said.

Roskamp historically has given the institute about one-third of its operating budget, the rest coming through grants and contracts.

But as federal money has been diverted elsewhere, and the institute's work has grown more complex, Roskamp has had to pick up more of the tab. He gave just over $1 million in 2005, but $4.6 million this year, he said.

His involvement began with funding a lab at the University of South Florida, then a teaching position eventually filled by Mullan.

In 2003, the institute left the university amid personnel and bureaucratic disputes and moved into the former Bausch & Lomb building in southern Manatee County. Roskamp said university overhead was too expensive, and that scientists can work faster in the independent setting.

"You bring your entrepreneurial hat to this kind of research," he said. "We're results-oriented people."

The scientists appreciate not having to wait for grants and approvals.

"We have the funding from Bob and Diane that allow us to move forward very quickly when we make a new discovery," Crawford said. "We are really free to focus on the research."

Paddling mice

Most Alzheimer's researchers now focus on a protein known as beta-amyloid that forms when a chemical process goes awry. The protein clumps together outside neurons, eventually killing those memory cells.

Mullan and Crawford were part of a team that in 1991 published papers establishing a link between a human gene, on chromosome 21, and early onset of the disease in patients in their 40s and 50s.

A year later, after they came to the United States, they published a paper looking at another genetic link to early-onset Alzheimer's.

The research made beta-amyloid a prime suspect in Alzheimer's, and stopping its buildup a potential cure.

Roskamp researchers look for existing drugs and new compounds with that effect. Nilvadipine showed enough promise to test it on lab mice engineered to have Alzheimer's.

At 10 months, with the disease in full bloom, some mice got the drug while others got a placebo. Later, they scanned the mice's brains for blood flow.

In the color-coded pictures, the brighter the image, the better the blood flow. The mice getting Nilvadipine scan largely red and orange.

The control animals scan mostly blue-green.

Mullan points to a chart with results of a more traditional test, tracking a mouse's effort to paddle its way out of a mouse-sized swimming pool.

The mice repeat the test, day after day. Normal mice figure it out and eventually swim a shorter route to the exit.

Mice with Alzheimer's disease never figure it out, actually taking longer and longer routes.

"But if you give them Nivaldipine, they go from here to here; they do better," Mullan said, pointing at the figures. "And if you give Nilvadipine to a normal mouse, they do best of all."

The drug appears to slow or stop the production of beta-amyloid, Mullan said.

As the brain grudgingly yields the mysteries of its architecture, Roskamp's scientists are exploring how those diseases of the mind may be related by more than just words.

'Blocking that burst'

In 2002 the institute teamed with the Department of Veterans Affairs to look at memory skills in people who had received traumatic brain injuries.

They found that people who had a gene linked to Alzheimer's disease recovered less memory function than those without it, even when they had comparable injuries and demographics.

Further research has shown that when the brain suffers such an injury, there is a burst of amyloid production. One theory is that the brain produces the protein as a defense mechanism, but it sometimes overreacts and makes matters worse.

"Blocking that burst appears to be at least one way to try and improve outcomes after head injury," said Crawford, lead author of the 2002 article.

Last year the Department of Defense approved a $1.5 million grant to the institute to expand that research. It is a particularly urgent matter for the military: Improved body armor is helping soldiers survive explosions -- but with little-understood head injuries.

"People can have brain injury even if they didn't suffer any loss of consciousness, weeks and months of being in the vicinity of an explosive attack," Crawford said.

For now, that grant is hung up in final reviews.

"We have yet to see dime one," Roskamp said -- but even that $1.5 million pales in comparison with the costs of the Nilvadipine study.

That cuts to the heart of the dilemma scientists face. They might get a moderately effective drug to market quickly, or try to discover the "silver bullet," which could take many years and exponentially more money.

Roskamp is preparing the foundation to do both.

Just a question of when

To Mullan, the question is not whether there will be treatments for Alzheimer's.

"It's the question of when we're going to get them there," he said.

It is a question of how effective they will be. Mullan cited three drugs far along in the pipeline, all targeted at reducing amyloid. "They're not going to be block-busting, perfect drugs by any means, but I think at least two of them will be approved for Alzheimer's this year."

Nilvadipine most likely would be like them -- useful but not the cure-all. But it offers some advantages.

Developing a new drug from scratch is a much worse bet, Mullan said. Count on 10 to 12 years for development, testing and approvals, with a high failure rate.

"Sometimes they fail spectacularly," he said, citing Vioxx, a promising drug with unforeseen and deadly side effects.

Nilvadipine, in use for more than a decade, already has a track record for safety. It could help patients while allowing the institute time to find the silver bullet.

By mid-year, the institute hopes to continue the Ireland trial with a double-blind study, meaning neither patients nor doctors know who gets Nilvadipine and who gets a placebo until they conclude. That study, which would involve about 200 people, could cost $20 million, Roskamp said.

Should the drug prove effective, Nilvadipine's manufacturer could profit -- but so would the institute. Because it holds rights to the drug's newly indicated use, the institute would receive royalty payments, Roskamp said.

The institute has set up a for-profit subsidiary, Roskamp Research LLC, which holds its patents. Roskamp structured it to allow outside backers to support studies, provide the subsidiary with a return on its investment, and guarantee most of the revenue goes to his institute.

"We don't want to give it to a pharma company, and say here, go make a lot of money off of it," Roskamp said.

Compounds back in the institute's labs could provide better returns -- and better treatments.

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Sarasota’s Roskamp Institute Releases Study Defining a Mechanism for Development of Obesity and the Metabolic Syndrome, Forerunners of Type 2 Diabetes

Sarasota, Fla. – August 1, 2007 The Roskamp Institute released a study defining a mechanism for the development of obesity and the metabolic syndrome, which are the forerunners of type 2 diabetes. The study, led by Roskamp’s Dr. Robert Farese, is detailed in the August issue of The Journal of Clinical Investigation, a highly prestigious medical research journal.

While the Roskamp Institute’s primary focus is on Alzheimer’s disease, Roskamp researchers have a significant interest in diabetes due to studies that suggest those who have diabetes are more likely to develop Alzheimer’s disease.

The study found that a deficiency in an enzyme, atypical protein kinase C, impairs the ability of insulin to stimulate glucose uptake into the muscle, which produces a state of resistance to circulating insulin. Once this occurs, the liver begins to produce excessive quantities of fat, causing abdominal obesity and alterations in blood lipids. According to the study, this can then lead to obesity and the metabolic syndrome, the precursors of type 2 diabetes.

“Although this gene-knockout study was done on mice, it is particularly relevant to type 2 diabetic humans, who are known to have deficiencies of this enzyme in their muscles,” said Dr. Farese. “The findings showed that in the mice a simple loss of one or more genes that are responsible for the production of this enzyme could eventually cause obesity and the metabolic syndrome which then could lead to type 2 diabetes.”

Further research must be done to determine how human diabetics acquire a deficiency of this enzyme in their muscles; however, this mouse model should be especially helpful to further study and devise treatments for obesity and the metabolic syndrome.

“We are particularly excited about this study and the potential to develop treatments for obesity and the metabolic syndrome, which are both global health problems,” said Dr. Michael Mullan, director of the Roskamp Institute. “This study will also be helpful in further determining how obesity, the metabolic syndrome and type 2 diabetes are linked to Alzheimer’s disease.”

The study was co-authored by Dr. Farese, who led the team of Mini P. Sajan, Hong Yang, and Sonali Nimal at the Roskamp Institute; and others at the James A. Haley Veterans Administration Medical Center in Tampa; the University of South Florida College of Medicine; the Joslin Research Foundation and Harvard University School of Medicine; Yale University School of Medicine, and Research Center at Oslo, Norway.

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The Roskamp Institute

The Roskamp Institute, a not-for-profit research Institute, is dedicated to finding cures for neuropsychiatric disorders, with the emphasis on Alzheimer’s disease (AD). Current research at the Roskamp Institute is focused on dissecting the molecular biological pathways implicated in AD pathogenesis in order to develop therapeutic targets specific to AD etiology. Dr. Michael Mullan (Director of the Roskamp Institute) and Fiona Crawford (Associate director of the Roskamp Institute) were part of the original team that discovered a genetic error called the “Swedish mutation” which results in overproduction of -amyloid (A) by aberrant proteolytic processing of the amyloid precursor protein (APP). This mutation now forms the bases of most mouse model of Alzheimer’s disease. Previously, the Roskamp Institute published an article in a prestigious scientific journal, Nature, showing that A plays a normal role in vasoactive mechanisms but also plays a role in vascular abnormalities and neurodegeneration mediated by free radical. Subsequently, Dr. Daniel Paris, a senior scientist at the Roskamp Institute, discovered that the vasoactive effects of A are partly mediated via a pro-inflammatory pathway and showed that this effect of A on the vasculature can be blocked by inhibiting specific target molecules. In order to further understand the role of A in the vasculature, Dr. Paris investigated the long term effect of A on vascular homeostasis. He then discovered that at low doses, A promotes angiogenesis, while at high doses, certain forms of A peptides are anti-angiogenic. Collectively, these novel findings resulted in new therapeutic prospects for the treatment of Alzheimer’s disease as well as Cancer.
Researchers at the Roskamp Institute also showed that the presence of functional CD40/CD40L signaling is essential for the full development of AD like pathology in transgenic mouse models of AD. In particular, it was demonstrated that accumulation of cerebral A is reduced in transgenic mouse models of AD by genetically or pharmacologically reducing the availability of CD40L to CD40. The Roskamp Institute investigators subsequently revealed that loss of functional CD40L diminishes both APP processing to A and microglial activation in the brain (Original findings published in journals Science and Nature Neuroscience). CD40L activated pathways in the presence of A appear to mediate both of these effects as well as the hyperphosphorylation of murine tau in vivo at epitopes analogous to those which precede tangle formation of human tau. More recently, Dr. Ghania Ait-Ghezala of the Roskamp Institute showed that CD40/CD40L interaction also affects APP via the NF-B pathway. Using NF-B inhibitors and SiRNAs to silence diverse elements of the NF-B pathway, she demonstrated that reduction in levels of both pathological forms of A. These results showed that CD40L stimulation may be a key component in AD pathology and that NF-B pathway may be suitable targets for therapeutic approaches against AD.
Another major focus of research at the Roskamp Institute includes Traumatic Brain Injury (TBI) Program headed by the Associate Director of the Roskamp Institute. Dr. Crawford and her Roskamp Institute team demonstrated an important relationship between apolipoprotein E (APOE) and memory following TBI. She demonstrated that in Veteran’s with TBI, memory performance was significantly worse in individuals who had at least one copy of APOE ε4 allele than those who did not. She had subsequently been funded through the Veteran’s Administration to further study the relationship between different forms of APOE in TBI with the emphasis on finding treatments for this devastating condition.
Drs. Michael Mullan and Fiona Crawford also received funding by the Counterdrug Technology Assessment Center (CTAC) to evaluate the newly emerged genomics and proteomics technology and find biological markers of substance abuse. Recently, Dr. Crawford’s team showed that cocaine treatment of human progenitor neuronal cells results in increased oxidative stress (possibly mediated by inflammatory responses) which precedes cell death. Thus, these findings may have implications for the consequences of cocaine abuse in situations where antioxidant capacity is compromised, as in the aging brain.
As evident here, the Roskamp Institute team has been a pioneer in many area of research in neuropsychiatric diseases and will continue to do so to find novel therapies for these disorders. Currently, a new clinical trial based on the discoveries made at the Roskamp Institute is underway to assess safety and efficacy of nilvadipine in treatment of Alzheimer’s disease. Through the generous support of Diane and Robert Roskamp, the Veteran’s Administration, the National Institutes of Health, CTAC and the Department of Defense, the Roskamp Institute will continue to provide potential avenues for novel therapeutic interventions for neuropsychiatric disorders.

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Roskamp Institute on Gulf War Illness

The Roskamp Institute located in Sarasota, Florida is the leading research center in the area. The research focuses on neurological diseases that affect young and elderly men and women of this world. Some of the main focuses are Alzheimer's disease, addiction, post-traumatic stress disorder (PTSD), multiple scoliosis, Gulf War syndrome and many more. The Director Dr. Michael Mullan leads his team of researchers to exciting findings. Recently the Institute has been given a grant from the VA for their research involving Gulf War Illness. This Illness that inflicts the soldiers that fought during the Gulf War affects their motor skills, memory, stability and other problematic symptoms. How the Illness commenced was through the combination of the neurotoxins and pesticides given to the soldiers. The research done in the Institute led to the finding that shows the toxic mixture affects the long fatty acid chains within the brain. Research continues within the walls of the 42,000 sq. ft research facility hopefully terminating the life altering Illness for our Veterans.

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Roskamp Institute Scientists Discover Genetic and Biological Consequences of Substance Abuse

A 2004 National Survey on Drug Use and Health reported that about 34 million Americans have had some exposure to cocaine at least once in their lifetime. The addictive properties of this drug is well recognized and results in an increased direct cost in medical care as well as indirect cost due to increased societal burden. The Roskamp Institute, located in Sarasota Florida is currently engaged in research into discovery of biological biomarkers and novel treatments for substance abuse. Michael Mullan MD PhD (Director of the Roskamp Institute), during his medical training in London, worked on addiction and determined that certain addictive disorders had a significant genetic component. It is now well-established that substance dependency has a prominent genetic component and approximately 40-60% of the vulnerability to substances can be sufficiently attributed to these genetic factors. Previously, the Roskamp Institute scientists demonstrated that a polymorphism in gene for mu-opioid receptor (OPRM1 +118A) is a risk for alcohol dependency. This Roskamp Institute team then examined the frequency of OPRM1 +118A carrying genotypes and alleles in several groups of substance-dependent cases compared to individuals with no history of reported substance abuse. These Roskamp Institute scientists found that the OPRM1 +118 polymorphism is a genetic risk factor for substance dependence but not specific to a particular substance (findings published in the journal Molecular Psychiatry).

Dr. Fiona Crawford (Associate director, Roskamp Institute) and Dr. Michael Mullan (Director, Roskamp Institute) received an award from the Counterdrug Technology Assessment Center (CTAC) to evaluate the newly emerged genomics and proteomics technologies and determine their usefulness in finding potential biomarkers and treatments for substance abuse. Dr. Fiona Crawford along with her Roskamp Institute team using this genomic technology investigated the fundamental transcriptional responses occurring in neurons as a consequence of acute cocaine exposure over a time period. These Roskamp Institute scientists used GeneChip Operating Software from Affymetrix to compare the genomic response in neuronal cells exposed to cocaine compared to cells that were not exposed and showed a time-dependent increase of genes associated with pro-inflammatory and immune responses. These findings suggest that the inflammatory and immune systems maybe involved in modulating response to an acute cocaine exposure (originally published in the Journal of Neurochemistry).

Next, this Roskamp Institute team determined a role of oxidative stress in cocaine exposure in human progenitor neuronal cells. Although, it is evident that cocaine induces oxidative stress in the central nervous system, little is known whether such increase in oxidative stress is also relevant to cell death in cocaine-exposed models. To gain further insight into the role of cocaine-induced oxidative stress, the Roskamp Institute scientists hypothesized that oxidative stress precedes cell death upon cocaine exposure and demonstrated that oxidative stress was significantly increased in neuronal cells treated with cocaine and this phenomenon preceded cell death. Therefore, these findings have implications for cocaine abuse in circumstances where antioxidant system is compromised, as in the aging brain (original findings in the Journal of Neurochemistry International).

The addictive properties of these psychoactive substances is well recognized and results in enormous burden of direct and indirect costs to the US economy. The Roskamp Institute is dedicated to understanding the factors that predispose individuals to substance abuse as well as discover additional molecular targets for therapeutic intervention.

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