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Intravenous Immunoglobulin Reduces Tau Pathology and Preserves Neuroplastic Gene Expression in the 3xTg Mouse Model of Alzheimer’s Disease

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Despite recent negative results of the Gammaglobulin Alzheimer's Partnership (GAP) trial, the good tolerability to intravenous immunoglobulin (IVIG) and its potential benefit for patient subpopulations have highlighted the importance of understanding IVIG’s mechanism of action. IVIG contains antibodies to amyloid suggesting an amyloid clearance mechanism. However, the suboptimal results of the amyloid immunotherapy trials suggest an additional mechanism. Therefore, we tested whether IVIG alters the expression of tau neurofibrillary tangle (NFT)-like deposits within hippocampal CA1 neurons of the 3xTg mouse model of AD. Three-month-old mice were treated intravenously with IVIG (10%, 400 mg/kg) or placebo (10% BSA/saline) every two weeks for either three or six months. At sacrifice, plasma was isolated for gene expression profiling and brains were processed for immunohistochemistry using the AT-180 antibody, which recognizes hyperphosphorylated tau in NFTs. Stereologic analysis of CA1 neurons following three months of treatment revealed no difference in AT-180+ neuron number but a significant 15-20% decrease in AT-180 intraneuronal optical density with IVIG compared to placebo. By contrast, the number of AT-180+ CA1 neurons was reduced by 25- 30% following six months of IVIG treatment compared to placebo. Expression profiling studies showed that IVIG treatment resulted in a significant 40-50% increase in plasma levels of genes regulating neuronal cytoskeletal plasticity function and calcium-mediated signaling compared to placebo. Moreover, several transcripts encoding protein phosphatase subunits were 40-50% higher in IVIG-treated mice. Hence, IVIG reduces hippocampal NFT pathology in the 3xTg mouse through a mechanism that may involve preservation of neuronal plasticity and tau phosphorylation homeostasis.
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Keywords: Alzheimer; gene array; hippocampus; immunoglobulin; neurofibrillary tangle; neuroplasticity; therapy

Document Type: Research Article

Publication date: September 1, 2014

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  • Current Alzheimer Research publishes peer-reviewed frontier review and research articles on all areas of Alzheimer's disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer's disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer's disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer's disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer's disease. Current Alzheimer Research provides a comprehensive 'bird's-eye view' of the current state of Alzheimer's research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.
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