A Therapeutic Role for Apolipoprotein-E in the Germ Theory of Alzheimer's Dementia

载脂蛋白-E 在阿尔茨海默氏痴呆病菌理论中的治疗作用

• 批准号: 10601779
• 负责人: Michael P. Vitek
• 金额: $ 50万
• 依托单位: REGENNOVA, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601779
• 关键词: Adult; Affect; African American population; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Amyloid; Amyloid beta-Protein; Animal Model; Anti-Bacterial Agents; Anti-Inflammatory Agents; Apolipoprotein E; Arginine; Bacteria; Bacterial DNA; Bacterial Infections; Binding; Blood; Brain; Brain Pathology; Caspase; Cell Surface Proteins; Cell surface; Clinic; Communicable Diseases; DNA; Data; Deposition; Disease; Dose; Encephalitis; Germ; Gingivitis; Goals; Gram-Negative Bacteria; Grant; Growth; In Vitro; Infection; Inflammation; Inflammatory; Invaded; Irrigation; Learning; Ligands; Link; Lipopolysaccharides; Longevity; Lysine; Measures; Memory; Minimum Inhibitory Concentration measurement; Modeling; Mus; Oral; Oral Administration; Oral cavity; Outcome; Pathogenicity; Pathology; Patients; Peptides; Performance; Periodontal Diseases; Peripheral; Phase; Porphyromonas gingivalis; Proteins; Qi; Reporting; Ribosomal RNA; Risk; Risk Reduction; Role; Route; Safety; Sepsis; Streptococcus cristatus; Symptoms; Testing; Therapeutic; Tissues; Tooth Loss; Toxicology; United States; Wild Type Mouse; aerobic respiration control protein; blood-brain barrier crossing; cecal ligation puncture; clinically relevant; commensal bacteria; comparison control; cytokine; dementia risk; design; efficacy evaluation; experimental study; gingipain; human old age (65+); improved; inhibitor; mimetics; mouse model; mutant; neuron loss; novel; novel strategies; oral infection; pathogenic bacteria; peptidomimetics; preference; tau-1; theories; virulence gene; Adult; Affect; African American population; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Amyloid; Amyloid beta-Protein; Animal Model; Anti-Bacterial Agents; Anti-Inflammatory Agents; Apolipoprotein E; Arginine; Bacteria; Bacterial DNA; Bacterial Infections; Binding; Blood; Brain; Brain Pathology; Caspase; Cell Surface Proteins; Cell surface; Clinic; Communicable Diseases; DNA; Data; Deposition; Disease; Dose; Encephalitis; Germ; Gingivitis; Goals; Gram-Negative Bacteria; Grant; Growth; In Vitro; Infection; Inflammation; Inflammatory; Invaded; Irrigation; Learning; Ligands; Link; Lipopolysaccharides; Longevity; Lysine; Measures; Memory; Minimum Inhibitory Concentration measurement; Modeling; Mus; Oral; Oral Administration; Oral cavity; Outcome; Pathogenicity; Pathology; Patients; Peptides; Performance; Periodontal Diseases; Peripheral; Phase; Porphyromonas gingivalis; Proteins; Qi; Reporting; Ribosomal RNA; Risk; Risk Reduction; Role; Route; Safety; Sepsis; Streptococcus cristatus; Symptoms; Testing; Therapeutic; Tissues; Tooth Loss; Toxicology; United States; Wild Type Mouse; aerobic respiration control protein; blood-brain barrier crossing; cecal ligation puncture; clinically relevant; commensal bacteria; comparison control; cytokine; dementia risk; design; efficacy evaluation; experimental study; gingipain; human old age (65+); improved; inhibitor; mimetics; mouse model; mutant; neuron loss; novel; novel strategies; oral infection; pathogenic bacteria; peptidomimetics; preference; tau-1; theories; virulence gene

Abstract: A Therapeutic Role for Apolipoprotein-E in the Germ Theory of AD P. gingivalis is the keystone bacteria of periodontal disease, the 6th most common infectious disease worldwide. Half of all Americans over the age of 30 and 70% of those over age 65 suffer some degree of P. gingivalis infection associated with gum disease. In a study of 6800 patients with gum disease that were followed for up to 26 years, those that developed gingivitis and then periodontal disease were linked to a significantly increased risk of dementia including Alzheimer's dementia. Tooth loss, a frequent outcome of periodontal disease, was also associated with an increased the risk of dementia. P. gingivalis products including lipopolysaccharide, cysteine proteases known as gingipains, and 16S rRNA from P. gingivalis have all been found in the brains of Alzheimer's patients. Since P. gingivalis is found in the mouth, the blood and is known to invade non-oral tissues including the brain, then strategies to reduce P. gingivalis numbers and activities including reducing brain inflammation, are beginning to show positive effects on outcomes associated with AD in animal models and in the clinic. We recently discovered that small mimetics of Apolipoprotein-E (ApoE-mimetics) inhibited the growth and killed P. gingivalis bacteria. Other groups have reported similar anti-bacterial activities of ApoE-mimetics including our ApoE-mimetics. These anti-bacterial activities appear to correlate with anti-inflammatory activities of ApoE-mimetics reported by us and other groups. We reported that these ApoE-mimetics extended lifespan in mice subjected to whole body sepsis using a caecal ligation and puncture model. We also reported that these ApoE-mimetics cross the blood brain barrier where they reduce brain inflammation in multiple models of Alzheimer's disease. In this grant, we propose to preferentially kill P. gingivalis by a unique strategy. This strategy involves a targeting ligand that specifically binds to a unique cell surface protein on P. gingivalis that, when conjugated with our anti-bacterial ApoE-mimetics, provides a “targeted” anti-bacterial agent. We refer to the “P. gingivalis targeting motif” as a “gingi-tif” and the conjugation with an ApoE-mimetic with as an “ApoE-gingitif”. As proof- of-principle, we now show that the ApoE-gingitif known as RGN2002 retains bacterial killing activity and preferentially targets P. gingivalis killing over killing of commensal bacteria (Figure 9 and Table 2). We will synthesize additional ApoE-gingitif and gingitif-ApoE conjugates and use them to measure the minimum inhibitory concentrations (MICs) against P. gingivalis. We will also use these ApoE-gingitif and gingitif-ApoE conjugates to measure MICs against a non-pathogenic commensal bacteria also found in the mouth. The ratio of the MICs for killing pathogenic P. gingivalis versus non-pathogenic commensal bacteria will provide a quantitation of the preferential killing of P. gingivalis, which we call a “Preference Ratio.” (Table 2). Once our in vitro screen has selected an appropriate ApoE-gingitif or gingitif-ApoE conjugate, then we will test these conjugates in a whole mouse model of P. gingivalis infection. Since oral delivery of P. gingivalis resulted in increased amyloid beta peptide 1-42, increased phosphorylated-tau and increased cytokines, which are all found in Alzheimer's patient's brains, we will measure these products in the brains of P. gingivalis infected mice with and without ApoE-gingitif or gingitif-ApoE conjugate treatment. These results will permit us to determine the efficacy of this targeted “ApoE-gingitif-strategy” to reduce brain inflammation and pathology associated with AD and P. gingivalis infections.

摘要：载脂蛋白-E在AD的细菌理论中的治疗作用 牙龈疟原虫是牙周疾病的基石细菌，第六个最常见的传染病 全世界。在30岁以上的所有美国人中，有一半超过65岁。 牙龈感染与牙龈疾病有关。在对6800例牙龈疾病患者的研究中 紧随其后的26年，患有牙龈炎和牙周疾病的患者与 包括阿尔茨海默氏症在内的痴呆症风险大大增加了。牙齿脱落，经常的结果 牙周疾病也与痴呆症风险增加有关。牙龈疟原虫产品 包括脂多糖，半胱氨酸蛋白酶，称为牙aipans和牙龈疟原虫的16s rRNA具有 所有这些都在阿尔茨海默氏症患者的大脑中发现。由于牙龈疟原虫在嘴里发现，血液，是 已知会侵入包括大脑在内的非口腔组织，然后是减少牙龈疟原虫数量和的策略 包括减少大脑感染在内的活动，开始对相关结果显示积极影响 在动物模型和诊所中使用广告。 我们最近发现，载脂蛋白-E（APOE-MIMETICS）的小bimetics抑制了生长 并杀死牙龈疟原虫。其他小组报告了Apoe-Mimetics类似的抗细菌活性 包括我们的apoe-Mimetics。这些抗细菌活动似乎与抗炎 美国和其他团体报告的Apoe-Mimetics的活动。我们报告说这些apoe-Mimetics扩展了 使用Caecal结扎和穿刺模型，在全身败血症的小鼠中寿命。我们还报告了 这些Apoe-Mimetics穿越了血脑屏障，在其中减少了多个的脑感染 阿尔茨海默氏病的模型。 在这笔赠款中，我们建议通过独特的策略优先杀死牙龈疟原虫。该策略涉及 靶向特异性结合牙龈疟原虫上独特的细胞表面蛋白的配体，当结合时 借助我们的抗细菌APOE-MIMETICS，提供了“靶向”抗菌剂。我们指的是“牙龈疟原虫 作为“ gingi-tif”的靶向基序，并与apoe-Mimetic与“ apoe-gyitif”结合。 首先，我们现在表明，称为RGN2002的apoe-gyitif保留了细菌杀戮活动和 优先靶向牙龈疟原虫杀死，而不是杀死共生细菌（图9和表2）。我们将 合成其他apoe-gyitif和gingitif-apoe结合物，并使用它们来测量最小值 针对牙龈疟原虫的抑制浓度（MIC）。我们还将使用这些apoe-gyitif和gingitif-apoe 偶联以测量在口腔中发现的非致病性共生细菌的麦克风。比率 杀死致病性牙龈疟原虫与非致病性共生细菌的麦克风将提供 对牙龈疟原虫首选杀害的定量，我们称之为“偏好比”。 （表2）。一旦我们进入 体外屏幕选择了适当的apoe-gyitif或gingitif-apoe con轭，然后我们将测试这些 在整个牙龈疟原虫感染的小鼠模型中结合。由于口服牙龈疟原虫导致 淀粉样蛋白β胡椒1-42增加，磷酸化-TAU增加并增加的细胞因子，这都是 在阿尔茨海默氏症患者的大脑中发现，我们将在感染牙龈疟原虫的大脑中测量这些产品 接受和没有apoe-gyitif或gingitif-apoe结合治疗的小鼠。这些结果将使我们能够 确定该目标“ apoe-gyitif-strategy”的效率，以降低脑感染和病理 与AD和牙龈疟原虫感染相关。