Nicoll James A R, Wilkinson David, Holmes Clive, Steart Phil, Markham Hannah, Weller Roy O
Division of Clinical Neurosciences, University of Southampton, Southampton, UK.
Nat Med. 2003 Apr;9(4):448-52. doi: 10.1038/nm840. Epub 2003 Mar 17.
Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Abeta (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Abeta plaques; (ii) those areas of cortex that were devoid of Abeta plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Abeta-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Abeta immunotherapy in mouse models of AD and suggest that the immune response generated against the peptide elicited clearance of Abeta plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9).
β淀粉样肽（Aβ）在阿尔茨海默病（AD）的发病机制中起关键作用。在AD转基因小鼠模型中用Aβ进行免疫可减少大脑中与年龄相关的Aβ积累以及相关的认知障碍。在此，我们展示了用Aβ（AN - 1792）免疫后人类神经病理学的首次分析。与未免疫的AD病例（n = 7）相比，尽管该免疫病例具有AD的诊断性神经病理学特征，但仍显示出以下异常特征：（i）新皮质有广泛区域，Aβ斑块极少；（ii）那些没有Aβ斑块的皮质区域，缠结、神经毡丝和脑淀粉样血管病（CAA）的密度与未免疫的AD相似，但缺乏与斑块相关的营养不良性神经突和星形胶质细胞簇；（iii）在一些没有斑块的区域，Aβ免疫反应性与小胶质细胞有关；（iv）存在T淋巴细胞脑膜脑炎；（v）脑白质有巨噬细胞浸润。发现（i） - （iii）与AD小鼠模型中Aβ免疫治疗后所见的变化非常相似，表明针对该肽产生的免疫反应促使该患者体内Aβ斑块清除。T淋巴细胞脑膜脑炎可能与其他一些接受AN - 1792的患者所见的副作用相对应（参考文献7 - 9）。
