Immunization with amyloid-beta attenuates inclusion body myositis-like myopathology and motor impairment in a transgenic mouse model.
Immunization with amyloid-beta attenuates inclusion body myositis-like myopathology and motor impairment in a transgenic mouse model.
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DOI：
10.1523/jneurosci.1150-09.2009
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发表时间：
2009-05-13
期刊：
影响因子：
--
通讯作者：
LaFerla FM
中科院分区：
文献类型：
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作者：
Kitazawa M;Vasilevko V;Cribbs DH;LaFerla FM
包络体肌炎（IBM）是困扰老年人最常见的肌肉疾病，可导致骨骼肌缓慢但进行性变性，最终导致瘫痪。标志性的病理特征包括t细胞介导的炎症浸润和蛋白质的异常积累，包括骨骼肌中的淀粉样蛋白- β (Aβ)、tau、泛素化蛋白、载脂蛋白E和α-突触核蛋白。大量的研究表明，异常的Aβ积累有助于肌肉变性。在此，我们在转基因小鼠模型中研究了主动免疫促进a β从受影响的骨骼肌纤维中清除是否减轻了ibm样肌肉病理特征和运动损伤。我们报道，与未治疗的小鼠相比，主动免疫显著减少细胞内Aβ沉积并减轻运动损伤。我们目前的研究结果表明，Aβ低聚物在免疫小鼠受影响的骨骼肌中显著减少，从而有助于肌病的过程。此外，免疫小鼠体内产生的抗a β抗体在体外阻断了a β低聚物的毒性，为功能恢复提供了可能的关键机制。这些发现为Aβ是IBM病理和随后的骨骼肌变性的关键致病成分之一的假设提供了支持。
Inclusion body myositis (IBM), the most common muscle disease to afflict the elderly, causes slow but progressive degeneration of skeletal muscle and ultimately paralysis. Hallmark pathological features include T-cell mediated inflammatory infiltrates and aberrant accumulations of proteins, including amyloid-beta (Aβ), tau, ubiquitinated-proteins, apolipoprotein E, and α-synuclein in skeletal muscle. A large body of work indicates that aberrant Aβ accumulation contributes to the myodegeneration. Here we investigated whether active immunization to promote clearance of Aβ from affected skeletal muscle fibers mitigates the IBM-like myopathological features as well as motor impairment in a transgenic mouse model. We report that active immunization markedly reduces intracellular Aβ deposits and attenuates the motor impairment compared to untreated mice. Results from our current study indicate that Aβ oligomers contribute to the myopathy process as they were significantly reduced in the affected skeletal muscle from immunized mice. In addition, the anti-Aβ antibodies produced in the immunized mice blocked the toxicity of the Aβ oligomers in vitro, providing a possible key mechanism for the functional recovery. These findings provide support for the hypothesis that Aβ is one of the key pathogenic components in IBM pathology and subsequent skeletal muscle degeneration.