静脉注射免疫球蛋白减少Tau蛋白病理学并在阿尔茨海默病的3xTg小鼠模型上保留神经可塑性相关基因表达

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

Volume: 11 Issue: 7

Author(s): Scott E. Counts, Sylvia E. Perez, Bin He and Elliott J. Mufson

Affiliation:

关键词: 阿尔茨海默症，基因芯片，海马体，免疫球蛋白，神经元纤维缠结，神经可塑性，治疗

摘要: 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.

Cite this article as:

Counts E. Scott, Perez E. Sylvia, He Bin and Mufson J. Elliott, Intravenous Immunoglobulin Reduces Tau Pathology and Preserves Neuroplastic Gene Expression in the 3xTg Mouse Model of Alzheimer`s Disease, Current Alzheimer Research 2014; 11 (7) . https://dx.doi.org/10.2174/1567205011666140812114037