D'Andrea Michael R
Johnson and Johnson Pharmaceutical, Research and Development, Drug Discovery, Spring House, PA 19477-0776, USA.
Med Hypotheses. 2005;64(3):458-63. doi: 10.1016/j.mehy.2004.08.024.
A sole pathological event leading to Alzheimer's disease (AD) remains undiscovered in spite of decades of costly research. In fact, it is more probable that the causes of AD are the result of a myriad of intertwining pathologies. However, hope remains that a single awry event could lead to the many pathological events observed in AD brain tissues thereby creating the presentation of simultaneous pathologies. Age-related vascular diseases, which include an impaired blood-brain barrier (BBB), are a common denominator associated with various degrees of dementia, including AD. Recently, a key finding not only demonstrated the anomalous presence of immunoglobulin (Ig) detection in the brain parenchyma of AD tissues but, most importantly, specific neurons that showed degenerative, apoptotic features contained these vascular-derived antibodies. In addition, subsequent studies detected classical complement components, C1q and C5b-9, in these Ig-positive neurons, which also were spatially more associated with reactive microglia over the Ig-negative neurons. Thus, it is possible that the mere presence of anti-neuronal autoantibodies in the serum, whose importance had been previously dismissed, may be without pathological consequence until there is a BBB dysfunction to allow the deleterious effects of these autoantibodies access on their targets. Hence, these observations suggest autoimmunity-induced cell death in AD.
尽管经过数十年代价高昂的研究,导致阿尔茨海默病(AD)的单一病理事件仍未被发现。事实上,AD的病因更有可能是众多相互交织的病理状况的结果。然而,人们仍然希望一个单一的异常事件可能导致在AD脑组织中观察到的许多病理事件,从而呈现出同时存在的多种病理状况。与年龄相关的血管疾病,包括血脑屏障(BBB)受损,是与各种程度的痴呆症(包括AD)相关的一个共同特征。最近,一项关键发现不仅证明了在AD组织的脑实质中存在异常的免疫球蛋白(Ig)检测,而且最重要的是,显示出退行性、凋亡特征的特定神经元含有这些血管源性抗体。此外,后续研究在这些Ig阳性神经元中检测到经典补体成分C1q和C5b - 9,在空间上,它们也比Ig阴性神经元更与反应性小胶质细胞相关。因此,血清中抗神经元自身抗体的存在(其重要性此前已被忽视),在血脑屏障功能正常时可能没有病理后果,直到血脑屏障功能障碍,使这些自身抗体能够对其靶标产生有害影响。因此,这些观察结果提示AD中存在自身免疫诱导的细胞死亡。