BioCircuits Institute, University of California San Diego, La Jolla, CA, USA.
Neuroscientist. 2020 Oct-Dec;26(5-6):455-470. doi: 10.1177/1073858420908189. Epub 2020 Feb 28.
Although Alzheimer's disease (AD) was described over a century ago, there are no effective approaches to its prevention and treatment. Such a slow progress is explained, at least in part, by our incomplete understanding of the mechanisms underlying the pathogenesis of AD. Here, I champion a hypothesis whereby AD is initiated on a disruption of the blood-brain barrier (BBB) caused by either genetic or non-genetic risk factors. The BBB disruption leads to an autoimmune response against pyramidal neurons located in the allo- and neocortical structures involved in memory formation and storage. The response caused by the adaptive immune system is not strong enough to directly kill neurons but may be sufficient to make them selectively vulnerable to neurofibrillary pathology. This hypothesis is based on the recent data showing that memory formation is associated with epigenetic chromatin modifications and, therefore, may be accompanied by expression of memory-specific proteins recognized by the immune system as "non-self" antigens. The autoimmune hypothesis is testable, and I discuss potential ways for its experimental and clinical verification. If confirmed, this hypothesis can radically change therapeutic approaches to AD prevention and treatment.
尽管阿尔茨海默病（AD）在一个多世纪前就被描述过，但目前仍没有有效的预防和治疗方法。这种进展缓慢至少部分归因于我们对 AD 发病机制相关机制的理解不完整。在这里，我支持这样一种假说，即 AD 是由遗传或非遗传风险因素引起的血脑屏障（BBB）破坏引发的。BBB 破坏会导致针对位于与记忆形成和存储相关的异皮质和新皮质结构中的锥体神经元的自身免疫反应。适应性免疫系统引起的反应不足以直接杀死神经元，但可能足以使它们对神经纤维病理变得选择性脆弱。这一假说基于最近的数据，这些数据表明记忆形成与表观遗传染色质修饰有关，因此可能伴随着免疫系统识别的记忆特异性蛋白的表达，这些蛋白被视为“非自身”抗原。自身免疫假说具有可检验性，我讨论了其实验和临床验证的潜在方法。如果得到证实，这一假说可以从根本上改变 AD 预防和治疗的治疗方法。
