Transgenic expression of ¦Â1 antibody in brain neurons impairs age-dependent amyloid deposition in APP23 mice
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- 作者：Paolo Paganetti ; Julia Reichwald ; Dorothee Bleckmann ; Dorothee Abramowski ; Domenico Ammaturo ; Carmen Barske ; Simone Danner ; Maurizio Molinari ; Matthias M¨¹ller ; St¨¦phanie Papin ; Sabine Rabe ; Peter Schmid ; Matthias Staufenbiel
- 关键词：Alzheimer's disease ; Immunotherapy ; Brain amyloid ; APP processing ; A¦Â deposition ; A¦Â efflux
- 刊名：Neurobiology of Aging
- 出版年：2013
- 出版时间：December, 2013
- 年：2013
- 卷：34
- 期：12
- 页码：2866-2878
- 全文大小：2417 K
文摘
Heterologous expression of the functional amyloid beta (A¦Â) antibody ¦Â1 in the central nervous system was engineered to maximize antibody exposure in the brain and assess the effects on A¦Â production and accumulation in these conditions. A single open reading frame encoding the heavy and light chains of ¦Â1 linked by the mouth and foot virus peptide 2A was expressed in brain neurons of transgenic mice. Two of the resulting BIN66 transgenic lines were crossed with APP23 mice, which develop severe central amyloidosis. Brain concentrations at steady-state 5 times greater than those found after peripheral ¦Â1 administration were obtained. Similar brain and plasma ¦Â1 concentrations indicated robust antibody efflux from the brain. In preplaque mice, ¦Â1 formed a complex with A¦Â that caused a modest A¦Â increase in brain and plasma. At 11 months of age, ¦Â1 expression reduced amyloid by 97 % compared with age-matched APP23 mice. Interference of ¦Â1 with ¦Â-secretase cleavage of amyloid precursor protein was relatively small. Our data suggest that severely impaired amyloid formation was primarily mediated by a complex of ¦Â1 with soluble A¦Â, which might have prevented A¦Â aggregation or favored transport out of the brain.