Vitamin C and cognition in Alzheimer's disease

维生素 C 与阿尔茨海默病的认知

• 批准号: 8644779
• 负责人: Fiona Edith Harrison
• 金额: $ 28.75万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644779
• 关键词: Acetylcholine; Acute; Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease risk; Animal Model; Antioxidants; Ascorbic Acid; Attenuated; Behavioral; Behavioral Symptoms; Brain; Cell Death; Cognition; Cognitive; Cognitive deficits; Data; Development; Diet; Disease; Disease Progression; Genotype; Glutamates; Goals; Health; Human; Individual; Intake; Intervention; Intraventricular; Investigation; Lead; Learning; Longevity; Memory; Memory impairment; Mus; Nature; Neurofibrillary Tangles; Neuromodulator; Neurons; Neurotransmitters; Outcome; Oxidative Stress; Pathology; Population; Populations at Risk; Research; Risk; Role; Route; Scurvy; Senile Plaques; Sodium; Staging; Structure of choroid plexus; Symptoms; System; Testing; Therapeutic; Time; Transgenic Mice; Ventricular; Wild Type Mouse; aged; aging brain; amyloid pathology; ascorbate; base; brain tissue; cholinergic; design; improved; innovation; intraperitoneal; mouse model; neurochemistry; neuropathology; neuroprotection; normal aging; novel; novel therapeutics; presenilin-1; public health relevance; research study; sodium-dependent vitamin C transporter 2; stem; treatment strategy

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is associated with a build up of oxidative stress in addition to the classic neuropathological signs of amyloid plaques, neurofibrillary tangles and cell death. An adequate supply of antioxidants in the diet during the lifetime, and especially in at-risk populations may mitigate the risk of excess damage by oxidative stress, however, the exact roles of particular antioxidants have yet to be clarified. In the current application we propose to investigate the role of vitamin C (ascorbic acid; ASC) in the development of neuropathology and cognitive deficits in a mouse model of AD. Further we will investigate the therapeutic potential of ASC to treat memory impairments. ASC is transported across the choroid plexus and into neurons by the Sodium-dependent Vitamin C Transporter (SVCT2). The creation of new mouse lines that either lack, or carry additional copies of the SVCT2 permits us for the first time to investigate the effects of a long term decrease or increase in brain ASC level, by the same mechanism, and without risk of ill health due to scurvy. We will cross these mice with an established mouse model of AD, APP/PSEN1 mice, and investigate how differing ASC levels impact the development of learning and memory impairments and also concomitant neuropathological changes at early, mid-, and later stages of disease progression. We anticipate that these data will reinforce the necessity to promote adequate intake of ASC and other antioxidants throughout the life-span, but especially in at-risk individuals. More importantly the data will tell us how ASC interacts with disease pathology to offer this critical neuroprotection. Finally, we present evidence that ASC can act as a neuromodulator, and we propose to investigate the potential of ASC to act as a novel, acute treatment via interperitoneal, and intra-ventricular treatments. These data will provide evidence that ASC can be used as a non-toxic treatment to improve memory deficits in APP/PSEN1 mice, and to promote further investigation of their use in humans.

描述（由申请人提供）：阿尔茨海默氏病（AD）除了典型的淀粉样斑块、神经原纤维缠结和细胞死亡等神经病理学症状外，还与氧化应激的积累有关。在一生中，特别是在高危人群中，饮食中提供充足的抗氧化剂可能会减轻氧化应激造成的过度损害的风险，但是，特定抗氧化剂的确切作用尚未阐明。在当前的应用中，我们建议研究维生素 C（抗坏血酸；ASC）在 AD 小鼠模型神经病理学和认知缺陷发展中的作用。我们将进一步研究 ASC 治疗记忆障碍的治疗潜力。 ASC 通过钠依赖性维生素 C 转运蛋白 (SVCT2) 转运穿过脉络丛并进入神经元。缺乏或携带额外 SVCT2 拷贝的新小鼠品系的创建使我们首次能够通过相同的机制研究大脑 ASC 水平长期降低或升高的影响，并且没有健康不良的风险由于坏血病。我们将把这些小鼠与已建立的 AD 小鼠模型、APP/PSEN1 小鼠进行杂交，并研究不同的 ASC 水平如何影响学习和记忆障碍的发展，以及疾病进展早期、中期和晚期伴随的神经病理变化。我们预计这些数据将强化在整个生命周期中促进充分摄入 ASC 和其他抗氧化剂的必要性，特别是对于高危人群。更重要的是，这些数据将告诉我们 ASC 如何与疾病病理相互作用以提供这种关键的神经保护。最后，我们提供了 ASC 可以充当神经调节剂的证据，并且我们建议研究 ASC 通过腹膜间和心室内治疗作为一种新型急性治疗的潜力。这些数据将提供证据表明 ASC 可作为一种无毒治疗方法来改善 APP/PSEN1 小鼠的记忆缺陷，并促进其在人类中的进一步研究。

项目成果

Intravenous ascorbate improves spatial memory in middle-aged APP/PSEN1 and wild type mice.

静脉注射抗坏血酸可改善中年 APP/PSEN1 和野生型小鼠的空间记忆。

• 发表时间: 2014-05-01
• 影响因子: 2.7
• 作者: Kennard, John A;Harrison, Fiona E
• 通讯作者: Harrison, Fiona E

Vitamin C deficiency in the brain impairs cognition, increases amyloid accumulation and deposition, and oxidative stress in APP/PSEN1 and normally aging mice.

大脑中维生素 C 缺乏会损害 APP/PSEN1 和正常衰老小鼠的认知能力，增加淀粉样蛋白的积累和沉积以及氧化应激。

• 发表时间: 2015-04-15
• 影响因子: 5
• 作者: Dixit, Shilpy;Bernardo, Alexandra;Walker, Jennifer Michelle;Kennard, John Andrew;Kim, Grace Youngeun;Kessler, Eric Sean;Harrison, Fiona Edith
• 通讯作者: Harrison, Fiona Edith

Low brain ascorbic acid increases susceptibility to seizures in mouse models of decreased brain ascorbic acid transport and Alzheimer's disease.

在脑抗坏血酸转运减少和阿尔茨海默病的小鼠模型中，低脑抗坏血酸会增加癫痫发作的易感性。

• 发表时间: 2015-02
• 影响因子: 2.2
• 作者: Warner, Timothy A;Kang, Jing;Kennard, John A;Harrison, Fiona E
• 通讯作者: Harrison, Fiona E

A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer's disease.

对维生素 C 预防与年龄相关的认知能力下降和阿尔茨海默病的严格审查。

• 发表时间: 2012
• 作者: Harrison; Fiona E
• 通讯作者: Fiona E

Vitamin C facilitates dopamine neuron differentiation in fetal midbrain through TET1- and JMJD3-dependent epigenetic control manner.

维生素 C 通过 TET1 和 JMJD3 依赖的表观遗传控制方式促进胎儿中脑多巴胺神经元分化。

• 发表时间: 2015-04
• 作者: He, Xi;Kim, Mirang;Kim, Seon;Yi, Sang;Rhee, Yong;Kim, Taeho;Lee, Eun;Park, Chang;Dixit, Shilpy;Harrison, Fiona E;Lee, Sang
• 通讯作者: Lee, Sang