Anti-Amyloid-β Single-Chain Antibody Brain Delivery Via AAV Reduces Amyloid Load But May Increase Cerebral Hemorrhages in an Alzheimer's Disease Mouse Model.
Anti-Amyloid-β Single-Chain Antibody Brain Delivery Via AAV Reduces Amyloid Load But May Increase Cerebral Hemorrhages in an Alzheimer's Disease Mouse Model.
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DOI：
10.3233/jad-2011-110230
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
Fukuchi K
中科院分区：
文献类型：
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作者：
Kou J;Kim H;Pattanayak A;Song M;Lim JE;Taguchi H;Paul S;Cirrito JR;Ponnazhagan S;Fukuchi K
淀粉样β蛋白（Aβ）在脑中的积累被认为是阿尔茨海默病（AD）的病因。靶向Aβ的免疫疗法对于减少大脑中的Aβ具有很大的希望。在此，我们评估了通过重组腺相关病毒（rAAV）递送抗A β单链抗体（scFv 59）在AD小鼠模型（TgAPPswe/PS1 dE 9）中减少Aβ沉积的有效性和安全性。首先，通过将rAAV血清型1、2和5注射到右侧脑室中来优化scFv 59向脑的递送。通过rAAV 1或rAAV 5在两个半球的整个海马和部分新皮质中发现了对称的高表达，而通过rAAV 2的scFv 59表达主要限于一个半球。然而，rAAV 1诱导细胞凋亡和小胶质细胞活化，而rAAV 5不诱导。因此，选择rAAV 5用于TgAPP swe/PS1 dE 9小鼠中的治疗性scFv 59递送。将rAAV 5类似地注射到10月龄TgAPPswe/PS1 dE 9小鼠的心室中，并在5个月后评估其有效性和安全性。海马中免疫反应性Aβ沉积减少。脑脊液（CSF）中Aβ42水平呈升高趋势，CSF中Aβ40：42比值降低，表明Aβ42从脑实质重新定位至CSF。在脑中发现与血管淀粉样蛋白局灶性增加相关的出血。虽然免疫治疗具有清除脑Aβ的巨大潜力，但应用rAAV介导的抗A β免疫治疗时应谨慎脑血管效应。
Accumulation of amyloid β-protein (Aβ) in the brain is thought to be a causal event in Alzheimer’s disease (AD). Immunotherapy targeting Aβ holds great promise for reducing Aβ in the brain. Here, we evaluated the efficacy and safety of anti-Aβ single-chain antibody (scFv59) delivery via recombinant adeno-associated virus (rAAV) on reducing Aβ deposits in an AD mouse model (TgAPPswe/PS1dE9). First, delivery of scFv59 to the brain was optimized by injecting rAAV serotypes 1, 2, and 5 into the right lateral ventricle. Symmetrical high expression of scFv59 was found throughout the hippocampus and partly in the neocortex in both hemispheres via rAAV1 or rAAV5 while scFv59 expression via rAAV2 was mostly limited to one hemisphere. rAAV1, however, induced apoptosis and microglial activation but rAAV5 did not. Therefore, rAAV5 was selected for therapeutic scFv59 delivery in TgAPPswe/PS1dE9 mice. rAAV5 was similarly injected into the ventricle of 10-month-old TgAPPswe/PS1dE9 mice and 5 months later its efficacy and safety were evaluated. Immunoreactive Aβ deposits reduced in the hippocampus. Aβ42 levels in cerebrospinal fluid (CSF) tended to increase and the Aβ40:42 ratio decreased in CSF, suggesting that Aβ42 was relocated from the parenchyma to CSF. Hemorrhages associated with a focal increase in blood vessel amyloid were found in the brain. While immunotherapy has great potential for clearing cerebral Aβ, caution for cerebrovascular effects should be exercised when rAAV-mediated anti-Aβ immunotherapy is applied.