Dietary manipulations in rabbits induce the cellular, neuropathological, and cognitive hallmarks of late-onset Alzheimer's Disease

兔子的饮食控制会诱发迟发性阿尔茨海默病的细胞、神经病理和认知特征

• 批准号: 10668423
• 负责人: BERNARD G. SCHREURS
• 金额: $ 54.89万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668423
• 关键词: Acetylcholinesterase; Adult; Affect; Alloxan; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Animals; Behavioral; Blood - brain barrier anatomy; Carrier Proteins; Characteristics; Chemicals; Cholesterol; Choline O-Acetyltransferase; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Complex; Data; Dementia; Dendritic Spines; Deposition; Diabetes Mellitus; Diet; Discrimination; Discrimination Learning; Dose; Electrophysiology (science); Epidemiology; Fatty acid glycerol esters; Female; Goals; Hepatotoxicity; High Fat Diet; Hippocampus; Human; Hyperglycemia; Hypertension; Impaired cognition; Impairment; Late Onset Alzheimer Disease; Learning; Life Style; Long-Term Potentiation; Membrane; Memory; Microglia; Modeling; Morphology; Neurobiology; Neuronal Plasticity; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oryctolagus cuniculus; Pathology; Plants; Positioning Attribute; Predictive Value; Prefrontal Cortex; Publishing; Research; Risk Factors; Rodent Model; Serum; Slice; Smoking; Soybean Oil; Superoxide Dismutase; Synaptic plasticity; Testing; Transgenic Mice; Translating; Ventricular; abeta accumulation; cerebrovascular; clinically relevant; cognitive function; comorbidity; dietary manipulation; eyeblink conditioning; feeding; human old age (65+); hypercholesterolemia; improved; innovation; lard; lipid transport; long term memory; male; mouse model; neuropathology; prevent; sugar; tau Proteins; translational potential; vascular inflammation; young adult

Abstract: Despite the significant contributions of transgenic mouse models to our understanding of Alzheimer’s disease, NIA has concluded that these models may be “of poor predictive value in human clinical trials” [RFA- AG-21-003]. As a result, there is a need for new, innovative, non-rodent, mammalian models that better recapitulate the cellular, neuropathological, and cognitive hallmarks of late-onset Alzheimer’s Disease (LOAD). These should include models in which risk factors for LOAD can be systematically induced, and in which cognitive deficits that are the earliest hallmarks of LOAD can be assessed. There is convincing epidemiological evidence that diet and lifestyle are important determinants of cognitive function, but it is unclear how factors such as high cholesterol, obesity, and diabetes increase the likelihood of cognitive deficits. The purpose of the current proposal is to develop, characterize, and validate unconventional, mammalian models that recapitulate the cellular, neuropathological, and cognitive hallmarks of LOAD. The strategy is to feed male and female rabbits a long-term, low-dose cholesterol diet in Aim 1, a high-fat diet in Aim 2, and a diet high in both sugar and fat in Aim 3 to recreate LOAD-like pathology and study the effects of hypercholesterolemia, obesity, and hyperglycemia on learning and memory using a range of increasingly complex tasks – well-understood paradigms that are altered in LOAD patients and we have shown to be affected by dietary manipulations in rabbits. We will also assess the cellular and neuropathological effects of hypercholesterolemia, obesity, and hyperglycemia including their impact on the neurobiology of learning and memory. Compelling preliminary data provide evidence that a short-term, high-dose cholesterol diet, a high-fat diet, and chemically-induced diabetes have deleterious effects on a range of learning and memory tasks. Preliminary electrophysiological evidence shows that feeding a diet high in cholesterol or high in fat can impair a well-known form of synaptic plasticity thought to underlie learning and memory – long-term potentiation. Published and preliminary pathophysiological data show significant diet- induced changes in cellular and neuropathological markers of LOAD. Taken together, these data provide proof of concept, but the levels of hypercholesterolemia and hyperglycemia were high and, although they recapitulated LOAD-like pathologies including beta amyloid accumulation, they also produced off-target pathology. It is therefore important to establish, characterize, and validate the cognitive and pathophysiological effects of milder, more long-term dietary manipulations that induce the types and levels of hypercholesterolemia, obesity, and hyperglycemia that are more clinically relevant. Our expertise in and track record of inducing significant behavioral, electrophysiological, and pathophysiological changes by manipulating diets in adult rabbits makes us well-suited to develop, characterize, and validate these unconventional models of LOAD – models that may represent improved translational potential by better replicating the cellular, neuropathological, and cognitive features of LOAD than current rodent models.

摘要：尽管转基因小鼠模型对我们对阿尔茨海默病的理解做出了重大贡献