Sigurdsson Einar M, Wisniewski Thomas, Frangione Blas
Department of Psychiatry, School of Medicine, New York University, 550 First Avenue, New York 10016, USA.
Neurobiol Aging. 2002 Nov-Dec;23(6):1001-8. doi: 10.1016/s0197-4580(02)00124-0.
Recent reports indicate that amyloid-beta (Abeta) vaccine-based therapy for Alzheimer's disease (AD) may be on the horizon. There are, however, concerns about the safety of this approach. Immunization with Abeta1-42 may not be appropriate in humans because it crosses the blood-brain barrier, can seed fibril formation, and is highly fibrillogenic. Abeta1-42 fibrils can in turn cause inflammation and neurotoxicity. This issue is of a particular concern in the elderly who often do not mount an adequate immune response to vaccines. Our findings show that vaccination with nonamyloidogenic/nontoxic Abeta derivative may be a safer therapeutic approach to impede the progression of Abeta-related histopathology in AD. Although the site of action of the anti-Abeta antibodies has been suggested to be within the brain, peripheral clearance of Abeta may have a greater role in reducing cerebral amyloid plaques in these animals and eventually in AD patients. Antibodies in general are predominantly found outside the central nervous system (CNS) and will, therefore, primarily clear systemic Abeta compared to brain Abeta. This disruption of the equilibrium between central and peripheral Abeta should then result in efflux of Abeta out of the brain, and subsequent removal of plaques. Abeta therapy can be targeted to the periphery, which may result in fewer CNS side effects, such as inflammation. Future Abeta derived vaccines should include T(h) epitopes, carriers and/or lipid moieties to enhance antibody production in the elderly, the population predominantly affected by AD.
最近的报告表明，基于淀粉样β蛋白（Aβ）疫苗的阿尔茨海默病（AD）治疗方法可能即将出现。然而，人们对这种方法的安全性存在担忧。用Aβ1-42进行免疫接种对人类可能并不合适，因为它能穿过血脑屏障，可引发纤维形成，且具有高度的纤维原性。Aβ1-42纤维反过来会引起炎症和神经毒性。这个问题在老年人中尤为令人担忧，他们通常对疫苗无法产生足够的免疫反应。我们的研究结果表明，用非淀粉样生成/无毒的Aβ衍生物进行疫苗接种可能是一种更安全的治疗方法，可阻止AD中与Aβ相关的组织病理学进展。尽管抗Aβ抗体的作用位点被认为在脑内，但Aβ的外周清除在减少这些动物以及最终AD患者的脑淀粉样斑块方面可能发挥更大作用。一般来说，抗体主要存在于中枢神经系统（CNS）之外，因此与脑内Aβ相比，它将主要清除全身的Aβ。中枢和外周Aβ之间平衡的这种破坏应会导致Aβ从脑内流出，随后斑块被清除。Aβ治疗可以靶向外周，这可能会减少中枢神经系统的副作用，如炎症。未来的Aβ衍生疫苗应包含辅助性T细胞（Th）表位、载体和/或脂质部分，以增强老年人（主要受AD影响的人群）的抗体产生。
