From the BioCircuits Institute, University of California San Diego, La Jolla, California.
J Neuropathol Exp Neurol. 2014 Mar;73(3):192-205. doi: 10.1097/NEN.0000000000000043.
Most ongoing efforts to combat Alzheimer disease (AD) are focused on treating its clinical symptoms, but the neuropathologic changes underlying AD appear decades earlier and become essentially irreversible by the time the disease reaches its clinical stages. This necessitates treating AD at preclinical stages, which requires a better understanding of the primary mechanisms leading to AD pathology. Here I argue that such an understanding calls for addressing perhaps the most puzzling question in AD-why the underlying pathology selectively impairs neurons that are involved in memory formation and storage. Memory formation is associated with epigenetic chromatin modifications and may, therefore, be accompanied by the synthesis of proteins unique to neurons involved in memory. These proteins could be recognized by the immune system as "nonself" antigens. This does not happen in the healthy brain because of its isolation from the immune system by the blood-brain barrier (BBB). All risk factors for AD impair the BBB, which may allow the immune system to attack memory-involved neurons and make them vulnerable to AD-associated pathology. This hypothesis is testable and, if confirmed, could redirect therapeutic efforts toward maintaining BBB integrity people belonging to AD risk groups rather than treating them when it is too late.
大多数针对阿尔茨海默病（AD）的现行防治措施主要集中在治疗其临床症状上，但 AD 潜在的神经病理学变化早在发病前几十年就已经出现，且当疾病进入临床阶段时，这些变化基本上是不可逆的。这就要求我们在疾病的临床前期进行治疗，这需要我们更好地理解导致 AD 病理的主要机制。在这里，我认为要想理解这一机制，就需要解决 AD 研究中最令人困惑的问题之一——为什么潜在的病理会选择性地损害参与记忆形成和存储的神经元。记忆的形成与表观遗传染色质修饰有关，因此可能伴随着与记忆相关的神经元特有的蛋白质的合成。这些蛋白质可能会被免疫系统识别为“非自身”抗原。然而，在健康的大脑中，这种情况不会发生，因为血脑屏障（BBB）将大脑与免疫系统隔离开来。所有 AD 的风险因素都会损害 BBB，这可能使免疫系统能够攻击与记忆相关的神经元，并使它们容易受到 AD 相关病理的影响。这一假设是可以验证的，如果得到证实，它可能会促使我们将治疗重点放在维持 AD 风险人群的 BBB 完整性上，而不是在为时过晚时才对他们进行治疗。
