Resveratrol for Enriching Neurogenesis & Memory in the Aged

描述（由申请人提供）：老年海马神经发生下降。由于新增加的神经元参与海马依赖的学习和记忆功能，与年龄相关的神经发生减少被认为是导致老年人认知功能障碍的原因。虽然衰老不会减少假定的海马神经干细胞/祖细胞（NSCs）的数量，也不会损害新生细胞的神经元分化和存活，但在衰老的海马中，静止的NSCs的百分比会增加。在这种情况下，确定安全的膳食补充剂，能够刺激静止的NSCs在老年海马中产生新的神经元，对于促进老年人认知功能的改善具有巨大的价值。白藜芦醇是一种在红葡萄皮中发现的具有强抗氧化和抗炎特性的植物抗毒素，它被认为是一种潜在的膳食补充剂，可以改善老年海马的神经发生，因为在衰老过程中，NSC可塑性的降低与活性氧和炎症的增加之间存在着明显的联系。此外，在消费者意识到饮用含白藜芦醇的红酒可以降低心脏病风险之后，白藜芦醇被推广为一种改善心血管健康的膳食补充剂。然而，其对神经干细胞和神经发生的影响尚不清楚。我们假设白藜芦醇可以促进老年海马NSC增殖和神经发生，从而改善认知功能。我们建议通过以下两个具体目标的高度定量实验来解决这一假设。在Specific Aim 1中，我们将量化老龄大鼠长期（28天）服用不同剂量白藜芦醇刺激NSCs增殖和增加海马神经发生程度的效果。在Specific Aim 2中，我们将确定长期服用白藜芦醇是否会改善老年认知功能障碍大鼠的学习和记忆功能。我们还将确定这些受损大鼠在白藜芦醇治疗后认知功能的增强是否与新生神经元进入海马记忆回路的增加和神经发生相关基因表达的增加有关。这些研究对于制定膳食补充剂策略以缓解老年人或老年阿尔茨海默病早期患者的海马相关认知障碍具有高度相关性。

DESCRIPTION (provided by applicant): Hippocampal neurogenesis declines in old age. As newly added neurons participate in hippocampal- dependent learning and memory functions, age-related decrease in neurogenesis is believed to contribute to cognitive dysfunction observed in the elderly. While aging does not reduce the numbers of putative hippocampal neural stem/progenitor cells (NSCs) or impair neuronal differentiation and survival of newly born cells, the percentage of quiescent NSCs increases in the aged hippocampus. In this context, identification of safe dietary supplements that have the ability to stimulate the quiescent NSCs to produce new neurons in the aged hippocampus has immense value for promoting improved cognitive function in the elderly. Resveratrol, a phytoalexin found in the skin of red grapes with potent antioxidant and anti- inflammatory properties, strikes as a potential dietary supplement for improving neurogenesis in the aged hippocampus because of the perceived link between reductions in NSC plasticity and increases in reactive oxygen species and inflammation during aging. Moreover, after the awareness of reduced cardiac risk in the consumers of Resveratrol-containing red wine, Resveratrol is being promoted as a dietary supplement for improving cardiovascular health. However, its effects on NSCs and neurogenesis are unknown. We hypothesize that Resveratrol administration in old age promotes hippocampal NSC proliferation and neurogenesis, which in turn leads to improved cognitive function. We propose to address this hypothesis through highly quantitative experiments in the following two specific aims. In Specific Aim 1, we will quantify the efficacy of long-term (28 days) administration of different doses of Resveratrol in aged rats for stimulating the proliferation of NSCs and increasing the extent of hippocampal neurogenesis. In Specific Aim 2, we will ascertain whether long-term administration of Resveratrol would improve learning and memory function in aged rats displaying cognitive dysfunction. We will also determine whether the enhanced cognitive function after Resveratrol treatment in these impaired rats is associated with increased incorporation of newly born neurons into the hippocampal memory circuitry and increased expression of neurogenesis-related genes. These studies are highly relevant towards developing dietary supplement strategies that ease hippocampal-related cognitive impairments in the elderly or in elderly patients with early stage of Alzheimer's disease. PUBLIC HEALTH RELEVANCE: This project will test the efficacy of long-term administration of Resveratrol in cognitively impaired aged rats for stimulating neural stem cell proliferation and improving hippocampal neurogenesis and cognitive function. These studies are relevant towards developing dietary supplement therapies that alleviate cognitive impairments in the elderly or in elderly patients with early stage of Alzheimer's disease.