Nontropic actions of neurotrophins: Subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation
Nontropic actions of neurotrophins: Subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation
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DOI：
10.1073/pnas.98.4.1941
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发表时间：
2001-02-13
影响因子：
11.1
通讯作者：
Tuszynski, MH
中科院分区：
文献类型：
--
作者：
Conner, JM;Darracq, MA;Tuszynski, MH
在灵长类动物中，正常衰老与认知功能的显著下降有关。然而，这种与年龄相关的神经功能下降的结构和分子基础尚未明确界定。在人类和非人类灵长类动物的正常衰老过程中并不会出现大量细胞丢失。近期更多研究表明，由于衰老，灵长类动物的皮质下脑区的功能性神经元标志物显著减少，包括多巴胺能和胆碱能系统，尽管尚未对这些神经元的皮质神经支配的相应损失进行研究。在本研究中，我们报告称，在恒河猴中，衰老与胆碱能系统的皮质神经支配显著减少25%有关（P < 0.001）。此外，通过将人神经生长因子递送至基底前脑的胆碱能胞体，这些与年龄相关的减少得到了改善，使皮质中胆碱能神经支配水平恢复到年轻猴子的水平（P = 0.89）。因此，（i）衰老与皮质胆碱能神经支配的显著减少有关；（ii）这种减少可通过生长因子的递送而逆转；（iii）生长因子能够远程重塑轴突终末区域，这代表了生长因子在调节成年神经元结构和功能方面的非向性作用（即，向胆碱能胞体施用生长因子可显著增加终末区域的轴突密度）。这些发现与生长因子治疗神经系统疾病的潜在临床应用相关。
Normal aging is associated with a significant reduction in cognitive function across primate species, However, the structural and molecular basis for this age-related decline in neural function has yet to be defined clearly. Extensive cell loss does not occur as a consequence of normal aging in human and nonhuman primate species, More recent studies have demonstrated significant reductions in functional neuronal markers in subcortical brain regions in primates as a consequence of aging, including dopaminergic and cholinergic systems, although corresponding losses in cortical innervation from these neurons have not been investigated. In the present study, we report that aging is associated with a significant 25% reduction in cortical innervation by cholinergic systems in rhesus monkeys (P < 0.001). Further, these age-related reductions are ameliorated by cellular delivery of human nerve growth factor to cholinergic somata in the basal forebrain, restoring levels of cholinergic innervation in the cortex to those of young monkeys (P = 0.89), Thus, (i) aging is associated with a significant reduction in cortical cholinergic innervation; (ii) this reduction is reversible by growth-factor delivery; and (iii) growth factors can remodel axonal terminal fields at a distance, representing a nontropic action of growth factors in modulating adult neuronal structure and function (i,e., administration of growth factors to cholinergic: somata significantly increases axon density in terminal fields), These findings are relevant to potential clinical uses of growth factors to treat neurological disorders.