Manev H
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 60612, USA.
Med Hypotheses. 2000 Jan;54(1):75-6. doi: 10.1054/mehy.1998.0824.
Recently, inflammatory pathways have been recognized as possible pathophysiological mechanisms of aging-associated neurodegenerations, and slowing of the progression of Alzheimer's disease can be achieved with anti-inflammatory drugs. The formation of endogenous inflammatory lipid mediators, leukotrienes, is initiated by 5-lipoxygenase (5-LOX), which is also expressed in neurons. We recently reported that aging is associated with a significant increase in neuronal 5-LOX gene expression and with increased, 5-LOX inhibitor-sensitive, vulnerability of neurons to degeneration. On the basis of these findings we have proposed that the 5-LOX pathway may influence the progression of aging-associated diseases, such as Alzheimer's. In humans, mutations of the promoter of the 5-LOX gene occur in a normal population with a frequency of about 25%. These mutations result in a decreased expression of the 5-LOX gene. Thus, it is hypothesized here that the onset of Alzheimer's disease will be delayed in subjects who display a mutation in the 5-LOX gene promoter, and that consequently the frequency of occurrence of the three known 5-LOX mutated alleles will be greater in subjects with onset of Alzheimer's at a very old age than in subjects with an earlier onset.
最近，炎症途径已被公认为是衰老相关神经退行性疾病可能的病理生理机制，并且使用抗炎药物可以减缓阿尔茨海默病的进展。内源性炎症脂质介质白三烯的形成由5-脂氧合酶（5-LOX）启动，5-LOX在神经元中也有表达。我们最近报道，衰老与神经元5-LOX基因表达的显著增加以及神经元对变性的5-LOX抑制剂敏感性增加有关。基于这些发现，我们提出5-LOX途径可能影响衰老相关疾病（如阿尔茨海默病）的进展。在人类中，5-LOX基因启动子的突变在正常人群中的发生频率约为25%。这些突变导致5-LOX基因表达降低。因此，本文假设在5-LOX基因启动子发生突变的受试者中，阿尔茨海默病的发病将延迟，因此，在非常高龄时发病的阿尔茨海默病患者中，三种已知的5-LOX突变等位基因的出现频率将高于发病较早的患者。
