New Jersey Institute for Successful Aging, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA.
J Alzheimers Dis. 2011;25(4):605-22. doi: 10.3233/JAD-2011-110098.
Previous studies have reported immunoglobulin-positive neurons in Alzheimer's disease (AD) brains, an observation indicative of blood-brain barrier (BBB) breakdown. Recently, we demonstrated the nearly ubiquitous presence of brain-reactive autoantibodies in human sera. The significance of these observations to AD pathology is unknown. Here, we show that IgG-immunopositive neurons are abundant in brain regions exhibiting AD pathology, including intraneuronal amyloid-β(42) (Aβ(42)) and amyloid plaques, and confirm by western analysis that brain-reactive autoantibodies are nearly ubiquitous in human serum. To investigate a possible interrelationship between neuronal antibody binding and Aβ pathology, we tested the effects of human serum autoantibodies on the intraneuronal deposition of soluble Aβ(42) peptide in adult mouse neurons in vitro (organotypic brain slice cultures). Binding of human autoantibodies to mouse neurons dramatically increased the rate and extent of intraneuronal Aβ(42) accumulation in the mouse cerebral cortex and hippocampus. Additionally, individual sera exhibited variable potency related to their capacity to enhance intraneuronal Aβ(42) peptide accumulation and immunolabel neurons in AD brain sections. Replacement of human sera with antibodies targeting abundant neuronal surface proteins resulted in a comparable enhancement of Aβ(42) accumulation in mouse neurons. Overall, results suggest that brain-reactive autoantibodies are ubiquitous in the blood and that a defective BBB allows these antibodies to access the brain interstitium, bind to neuronal surfaces and enhance intraneuronal deposition of Aβ(42) in AD brains. Thus, in the context of BBB compromise, brain-reactive autoantibodies may be an important risk factor for the initiation and/or progression of AD as well as other neurodegenerative diseases.
先前的研究报告称，阿尔茨海默病（AD）大脑中存在免疫球蛋白阳性神经元，这一观察结果表明血脑屏障（BBB）发生了破裂。最近，我们证明了人类血清中存在几乎普遍存在的脑反应性自身抗体。这些观察结果对 AD 病理学的意义尚不清楚。在这里，我们表明，在具有 AD 病理学的大脑区域中，存在大量 IgG 免疫阳性神经元，包括神经元内淀粉样β（42）（Aβ（42））和淀粉样斑块，并通过 Western 分析证实，脑反应性自身抗体在人类血清中几乎普遍存在。为了研究神经元抗体结合与 Aβ 病理学之间可能存在的相互关系，我们测试了人类血清自身抗体对可溶性 Aβ（42）肽在体外（器官型脑切片培养）成年小鼠神经元内沉积的影响。人类自身抗体与小鼠神经元的结合显著增加了 Aβ（42）在小鼠大脑皮层和海马中的神经元内积累速度和程度。此外，个体血清表现出与增强神经元内 Aβ（42）肽积累和免疫标记 AD 大脑切片中神经元的能力相关的可变效力。用针对丰富的神经元表面蛋白的抗体替代人血清导致 Aβ（42）在小鼠神经元中的积累得到类似的增强。总的来说，结果表明，脑反应性自身抗体在血液中普遍存在，并且有缺陷的 BBB 允许这些抗体进入脑间质，与神经元表面结合并增强 AD 大脑中 Aβ（42）的神经元内沉积。因此，在 BBB 受损的情况下，脑反应性自身抗体可能是 AD 以及其他神经退行性疾病的起始和/或进展的重要危险因素。
