Marked disparity between age-related changes in dopamine and other presynaptic dopaminergic markers in human striatum
Marked disparity between age-related changes in dopamine and other presynaptic dopaminergic markers in human striatum
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DOI：
10.1046/j.1471-4159.2003.02017.x
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发表时间：
2003-11-01
影响因子：
4.7
通讯作者：
Kish, SJ
中科院分区：
文献类型：
--
作者：
Haycock, JW;Becker, L;Kish, SJ
由于脑多巴胺能神经支配的年龄相关性变化被认为影响与多巴胺(DA)有关的人类疾病，因此我们测量了56名1天至103岁的神经学正常者死后纹状体(尾状核和壳核)中几种DA能标志物[DA、高香草酸、酪氨酸羟基酶(TH)、芳香L氨基酸脱羧酶(AADC)、囊泡单胺转运体2(VMAT2)和多巴胺转运体(DAT)]的水平。纹状体DA水平在青春期后显著升高(2-3倍)，然后在衰老过程中下降。同样，TH和AADC在出生后的头两年几乎增加了100%；然而，TH和AADC的水平在大约30岁时下降到成年水平。尽管VMAT2和DAT水平与TH水平密切相关，导致TH与转运蛋白的比率在发育和衰老过程中相对恒定，但DAT水平在衰老过程中仅在尾状核观察到轻微但显著的下降(13%)。这种突触前标记的出生后双相模式表明，纹状体DA能神经支配/神经束似乎在出生后继续发育良好，但似乎变得过于复杂，并在青春期经历退行性重塑。然而，在成年期，DA的丢失和参与其生物合成和区隔的蛋白质的相对保存之间观察到了显著的差异。这表明，成年期和衰老期间DA相关功能的下降可能是由DA本身而不是DA能神经管的损失来解释的。
Because age-related changes in brain dopaminergic innervation are assumed to influence human disorders involving dopamine (DA), we measured the levels of several presynpatic DAergic markers [DA, homovanillic acid, tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT)] in post-mortem human striatum (caudate and putamen) from 56 neurologically normal subjects aged 1 day to 103 years. Striatal DA levels exhibited pronounced (2- to 3-fold) post-natal increases through adolescence and then decreases during aging. Similarly, TH and AADC increased almost 100% during the first 2 post-natal years; however, the levels of TH and, to a lesser extent, AADC then declined to adult levels by approximately 30 years of age. Although VMAT2 and DAT levels closely paralleled those of TH, resulting in relatively constant TH to transporter ratios during development and aging, a modest but significant decline (13%) in DAT levels was observed in only caudate during aging. This biphasic post-natal pattern of the presynaptic markers suggests that striatal DAergic innervation/neuropil appears to continue to develop well past birth but appears to become overelaborated and undergo regressive remodeling during adolescence. However, during adulthood, a striking discrepancy was observed between the loss of DA and the relative preservation of proteins involved in its biosynthesis and compartmentation. This suggests that declines in DA-related function during adulthood and senescence may be explained by losses in DA per se as opposed to DAergic neuropil.