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）：阿尔茨海默病（AD）除了淀粉样斑块、神经纤维缠结和细胞死亡的经典神经病理学体征外，还与氧化应激的积累有关。一生中饮食中充足的抗氧化剂供应，尤其是在高危人群中，可能会降低氧化应激过度损伤的风险，然而，特定抗氧化剂的确切作用尚未明确。在本申请中，我们提出研究维生素C（抗坏血酸; ASC）在AD小鼠模型中神经病理学和认知缺陷的发展中的作用。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（SVCT 2）转运穿过脉络丛并进入神经元。缺乏或携带SVCT 2的额外拷贝的新小鼠品系的创建允许我们第一次通过相同的机制研究脑ASC水平长期降低或增加的影响，并且没有由于坏血病引起的健康不良的风险。我们将这些小鼠与已建立的AD小鼠模型APP/PSEN 1小鼠杂交，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，中期和后期伴随的神经病理学变化。我们预计，这些数据将加强促进在整个生命周期中摄入足够的ASC和其他抗氧化剂的必要性，特别是在高危人群中。更重要的是，这些数据将告诉我们ASC如何与疾病病理学相互作用，以提供这种关键的神经保护。最后，我们提出的证据表明，ASC可以作为一种神经调质，我们建议调查的潜力ASC作为一种新的，急性治疗，通过腹膜内，脑室治疗。这些数据将提供证据表明，ASC可用作无毒治疗，以改善APP/PSEN 1小鼠的记忆缺陷，并促进其在人类中使用的进一步研究。

项目成果

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

• DOI: 10.1002/stem.1932
• 发表时间: 2015-04
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: He, Xi-Biao;Kim, Mirang;Kim, Seon-Young;Yi, Sang-Hoon;Rhee, Yong-Hee;Kim, Taeho;Lee, Eun-Hye;Park, Chang-Hwan;Dixit, Shilpy;Harrison, Fiona E.;Lee, Sang-Hun
• 通讯作者: Lee, Sang-Hun

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

• DOI: 10.1021/cn500308h
• 发表时间: 2015-04-15
• 期刊: ACS CHEMICAL NEUROSCIENCE
• 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

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

• DOI: 10.3233/jad-2012-111853
• 发表时间: 2012
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Harrison FE

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

• DOI: 10.1016/j.eplepsyres.2014.11.017
• 发表时间: 2015-02
• 期刊: Epilepsy research
• 影响因子: 2.2
• 作者: Warner TA;Kang JQ;Kennard JA;Harrison FE
• 通讯作者: Harrison FE

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

• DOI: 10.1016/j.bbr.2014.01.044
• 发表时间: 2014-05-01
• 期刊: BEHAVIOURAL BRAIN RESEARCH
• 影响因子: 2.7
• 作者: Kennard, John A.;Harrison, Fiona E.
• 通讯作者: Harrison, Fiona E.