Lombardo Julianne A, Stern Edward A, McLellan Megan E, Kajdasz Stephen T, Hickey Gregory A, Bacskai Brian J, Hyman Bradley T
Center for Aging, Genetics, and Neurodegeneration, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
J Neurosci. 2003 Nov 26;23(34):10879-83. doi: 10.1523/JNEUROSCI.23-34-10879.2003.
The accumulation of amyloid-beta into insoluble plaques is a characteristic feature of Alzheimer's disease. Neuronal morphology is distorted by plaques: rather than being essentially straight, they are substantially more curved than those in control tissue, their trajectories become altered, and they are frequently distended or swollen, presumably affecting synaptic transmission. Clearance of plaques by administration of antibodies to amyloid-beta is a promising therapeutic approach to the treatment of Alzheimer's disease, leading to stabilization of dementia by an unknown cellular mechanism. The effect of plaque clearance on plaque-induced neuronal alterations has not been studied previously. Here we show that both plaques and neuritic lesions are reversible in a strikingly short period of time after administration of a single dose of amyloid-beta antibody. Amyloid clearance and recovery of normal neuronal geometries were observed as early as 4 d and lasted at least 32 d after a single treatment. These results demonstrate that, once plaques are cleared, neuronal morphology is self-correcting and that passive antibody treatment has the potential to reverse neuronal damage caused by Alzheimer's disease and, hence, directly impact cognitive decline. Moreover, the rapid normalization of neuritic dystrophy suggests an unexpected degree of plasticity in the adult nervous system.
淀粉样β蛋白聚积形成不溶性斑块是阿尔茨海默病的一个特征性表现。斑块会使神经元形态发生扭曲：与正常组织中的神经元相比，它们不再基本呈直线状，而是弯曲程度显著增加，其轨迹发生改变，并且经常出现扩张或肿胀，这可能会影响突触传递。通过给予抗淀粉样β蛋白抗体来清除斑块是一种很有前景的治疗阿尔茨海默病的方法，它通过一种未知的细胞机制使痴呆症状得到稳定。此前尚未研究过斑块清除对斑块诱导的神经元改变的影响。在此我们表明，在单次给予淀粉样β蛋白抗体后，斑块和神经炎性病变在极短的时间内都是可逆的。单次治疗后，最早在4天时就观察到淀粉样蛋白清除以及神经元恢复正常形态，并且至少持续32天。这些结果表明，一旦斑块被清除，神经元形态会自我纠正，被动抗体治疗有可能逆转由阿尔茨海默病导致的神经元损伤，从而直接影响认知衰退。此外，神经炎性营养不良的快速恢复表明成年神经系统具有出人意料的可塑性程度。
