Collier Timothy J, Lipton Jack, Daley Brian F, Palfi Stephane, Chu Yaping, Sortwell Caryl, Bakay Roy A E, Sladek John R, Kordower Jeffrey H
Department of Neurology, University of Cincinnati, PO Box 670525, 265 Albert Sabin Way, Cincinnati, OH 45267, USA.
Neurobiol Dis. 2007 Apr;26(1):56-65. doi: 10.1016/j.nbd.2006.11.013. Epub 2007 Jan 23.
Aging is the most prominent risk factor for Parkinson's disease. Yet, consensus of how advancing age may predispose the dopamine (DA) system to parkinsonism is lacking. Three age ranges of female rhesus monkeys, 8-9, 15-17, and 21-31 years, received unilateral DA depletion with intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Morphological and biochemical analyses of DA-depleted and intact hemispheres revealed three primary findings: (1) The intact striatum exhibited age-related declines in dopamine (DA) and homovanillic acid (HVA) that were present by middle age; (2) In the MPTP-treated striatum, the compensatory increase in DA activity was absent in old monkeys; and (3) Age-associated morphological changes included declines in the density of tyrosine hydroxylase (TH) positive fibers in striatum, decreased nigral soma size, and optical density of TH, but no significant loss of neurons. These findings suggest that aging produces changes in the nigrostriatal DA system that approach the threshold for expression of parkinsonian features, and that progressive impairment of plasticity may be central to the role of aging in development of parkinsonism.
衰老是帕金森病最显著的风险因素。然而，对于年龄增长如何使多巴胺（DA）系统易患帕金森症，目前尚无共识。对8 - 9岁、15 - 17岁和21 - 31岁三个年龄阶段的雌性恒河猴进行了单侧颈内注射1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶（MPTP）以耗尽多巴胺。对多巴胺耗尽和完整的半球进行形态学和生化分析，得出三个主要发现：（1）完整的纹状体在中年时就出现了与年龄相关的多巴胺（DA）和高香草酸（HVA）下降；（2）在MPTP处理的纹状体中，老年猴子没有出现多巴胺活性的代偿性增加；（3）与年龄相关的形态学变化包括纹状体中酪氨酸羟化酶（TH）阳性纤维密度下降、黑质细胞体大小减小以及TH的光密度降低，但神经元无明显丢失。这些发现表明，衰老会使黑质纹状体多巴胺系统发生变化，接近帕金森病特征表达的阈值，并且可塑性的逐渐受损可能是衰老在帕金森病发展中起作用的核心因素。
