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"NF-kB pathway may be suitable targets for therapeutic approaches against Alzheimer’s disease"


Article at Roskamp website:
The Roskamp Institute, a not-for-profit research Institute, is dedicated to finding cure for neuropsychiatric disorder, with the emphasis on Alzheimer’s disease (AD). Current research at the Roskamp Institute is focused on dissecting the molecular biological pathways implicated in Alzheimer’s disease pathogenesis in order to develop therapeutic targets specific to Alzheimer’s disease 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 “Swedish mutation” which results in overproduction of beta-amyloid (Abeta) by aberrant proteolytic processing of 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 Abeta 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 Abeta are partly mediated via a pro-inflammatory pathway and showed that this effect of Abeta on the vasculature can be blocked by inhibiting specific target molecules. In order to further understand the role of Abeta in the vasculature, Dr. Paris investigated the long term effect of Abeta on vascular homeostasis. He then discovered that at low doses, Abeta promotes angiogenesis, while at high doses, certain forms of Abeta 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 Alzheimer’s disease like pathology in transgenic mouse models of AD. In particular, it was demonstrated that accumulation of cerebral Abeta is reduced in transgenic mouse models of Alzheimer’s disease by genetically or pharmacologically reducing the availability of CD40 ligand to CD40. The Roskamp Institute investigators subsequently revealed that loss of functional CD40L diminishes both APP processing to Abeta and microglial activation in the brain (Original findings published in journals Science and Nature Neuroscience). CD40L activated pathways in the presence of Abeta 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-kB pathway. Using NF-kB inhibitors and SiRNAs to silence diverse elements of the NF-kB pathway, she demonstrated that reduction in levels of both pathological forms of Abeta. These results showed that CD40L stimulation may be a key component in Alzheimer’s disease pathology and that NF-kB pathway may be suitable targets for therapeutic approaches against Alzheimer’s disease . 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 Traumatic Brain Injury . She demonstrated that in Veteran’s with Traumatic Brain Injury , memory performance was significantly worse in individuals who had at least one copy of APOE epsilon4 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 Traumatic Brain Injury 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. Roskamp Institute is actively involved in Gulf War Syndrome or Gulf War Illness Research. Specifically the scientists are studying the effect of gulf war agents like PB & Permethrin on biological pathways using model organisms. You can read more about the research and clinical trials at: Roskamp Institute News and Articles . To learn more about Dr. Michael Mullan Alzheimer Research please visit Michael Mullan Alzheimer Research Notes or Michael Mullan Alzheimers Information website"

Article at:
http://www.roskampinstitute.us/