Burke W J, Park D H, Chung H D, Marshall G L, Haring J H, Joh T H
Department of Neurology, Veterans Administration Medical Center, St. Louis, MO.
Brain Res. 1990 Dec 24;537(1-2):83-7. doi: 10.1016/0006-8993(90)90342-9.
Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin and a specific marker for serotonergic neurons. These neurons are affected in Alzheimer's disease (AD) in several ways: serotonin is decreased in axon terminals, serotonin neurons accumulate neurofibrillary protein, and these neurons are lost in AD brains. One subcellular mechanism which may underlie degeneration of neurons in AD is decreased axonal transport with accumulation of enzymes and their potentially toxic metabolites in the cell body. To determine whether there is a defect in axonal transport in serotonin neurons in AD we measured TPH activity, serotonin and its oxidative metabolite 5-hydroxyindoleacetic acid (5-HIAA) in dorsal raphe cell bodies from Alzheimer and control cases. TPH activity is increased 4.7-fold in raphe neuron cell bodies in Alzheimer brains. Serotonin and 5-HIAA are increased by 4.0- and 2.0-fold, respectively in Alzheimer compared to control raphe cell bodies. In contrast, in synaptic terminals of the amygdala 5-HT and 5-HIAA were decreased by 41% and 50%, respectively in the same AD cases. We propose that the accumulation of TPH and its products in the raphe perikarya in AD results from a diminished transport of TPH to axon terminals. The accumulation of oxidative metabolites of serotonin may contribute to the degeneration of serotonergic neurons in AD.
色氨酸羟化酶（TPH）是血清素合成中的限速酶，也是血清素能神经元的特异性标志物。这些神经元在阿尔茨海默病（AD）中受到多种影响：轴突终末中的血清素减少，血清素神经元积累神经原纤维蛋白，并且这些神经元在AD脑内丢失。AD中神经元变性的一种亚细胞机制可能是轴突运输减少，导致酶及其潜在有毒代谢产物在细胞体内积累。为了确定AD中血清素能神经元的轴突运输是否存在缺陷，我们测量了阿尔茨海默病患者和对照病例中中缝背核细胞体中的TPH活性、血清素及其氧化代谢产物5-羟吲哚乙酸（5-HIAA）。在阿尔茨海默病脑的中缝神经元细胞体中，TPH活性增加了4.7倍。与对照中缝细胞体相比，阿尔茨海默病患者的血清素和5-HIAA分别增加了4.0倍和2.0倍。相比之下，在相同AD病例的杏仁核突触终末中，5-羟色胺（5-HT）和5-HIAA分别减少了41%和50%。我们提出，AD中中缝核周体中TPH及其产物的积累是由于TPH向轴突终末的运输减少所致。血清素氧化代谢产物的积累可能导致AD中血清素能神经元的变性。
