Virus and olfactory system interactions accelerate Alzheimer's disease pathology

病毒和嗅觉系统相互作用加速阿尔茨海默病病理学

• 批准号: 10669880
• 负责人: Maria Acena Nagel
• 金额: $ 103.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669880
• 关键词: Acceleration; Affect; Age; Age Years; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; American; Amyloid; Amyloid beta-Protein Precursor; Amyloid deposition; Anosmia; Antibodies; Antiviral Agents; Apoptosis; Behavioral; Biological; Biological Assay; Biopsy; Calcium; Cause of Death; Cells; Cerebrospinal Fluid; Cessation of life; Clinical; Cognitive; Coupled; Data; Dementia; Disease; Disease Progression; Electron Microscopy; Enzyme-Linked Immunosorbent Assay; Formalin; Frequencies; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genotype; Herpesvirus 1; Herpesvirus Type 3; Hippocampus; Human; Image; Immunohistochemistry; Impaired cognition; Individual; Infection; Inflammatory; Liquid substance; Literature; Macrophage; Mass Spectrum Analysis; Measures; Microglia; Mus; Nasal cavity; Nerve Degeneration; Neurites; Neuronal Differentiation; Neuronal Dysfunction; Olfactory Epithelium; Olfactory Pathways; Olfactory dysfunction; Olfactory tract; Paraffin; Pathologic Processes; Pathology; Pathway interactions; Peptides; Production; Proteins; Proteome; Proteomics; RNA; Risk Factors; Saliva; Sensory; Serum; Slide; Small Interfering RNA; Smell Perception; Statistical Data Interpretation; Testing; Time; Tissues; Traction; Transcript; Transfection; Up-Regulation; Vaccines; Viral; Virus; Virus Diseases; aged; cell type; chronic infection; cognitive change; cohort; comparison control; cost; cytokine; dementia risk; disability; disease phenotype; entorhinal cortex; familial Alzheimer disease; imaging system; interest; islet amyloid polypeptide; liquid crystal polymer; nano-string; neural; neurogenesis; neuroinflammation; olfactory bulb; olfactory sensory neurons; optogenetics; overexpression; potential biomarker; prevent; transcriptome; transcriptomics; treatment risk; varicella-zoster virus immediate early protein 62; viral DNA

PROJECT SUMMARY: Identification and treatment of risk factors that accelerate Alzheimer's disease (AD) are essential to slowing disease progression. Alphaherpesviruses (herpes simplex virus type 1 [HSV-1], varicella zoster virus [VZV]) are potential accelerators of AD because they increase dementia risk and produce similar pathologies, including amyloid, neuroinflammation, neurodegeneration, and cognitive impairment1-3. In parallel literature, early AD is characterized by smell loss4,5, amyloid deposition in olfactory epithelium (OE)6,7, and olfactory sensory neuron (OSN) dysfunction (reviewed in8). Because sniff-induced gamma () oscillations generated in olfactory bulb (OB) are directionally coupled to the hippocampus9-12, smell loss would result in decreased hippocampal  oscillations that have been postulated to lead to neurodegeneration and cognitive decline.14-16 Because alphaherpesviruses infect and reactivate in the nasal cavity, alphaherpesvirus disruption of olfactory pathways may accelerate AD. Our preliminary data show: (1) compared to controls, OB and olfactory tract (OT) from familial AD (FAD) subjects have upregulation of viral and inflammatory transcriptional pathways , confirmed at the protein level; (2) VZV immediate early protein 62 was detected in serum of 2 of 3 AD subjects and in 0/4 controls; (3) HSV-1- and VZV-infected human OE cultures (OECs) contain amyloid and increased OSN differentiation; and, (4) intranasal HSV-1-infected 5xFAD mice have increased OE amyloid and decreased olfaction compared to uninfected or pre-inoculation controls, respectively. Taken together, we hypothesize that alphaherpesvirus infection of the OE contributes to pathological processes within the olfactory system and hippocampus, thereby accelerating disease. To test this hypothesis, we will: (Aim 1) identify gene hippocampus, (Aim 2) determine whether infection of human OE with VZV and HSV-1 ex vivo elicits amyloid production and loss of odorant responsiveness, recapitulating smell loss in AD; and (Aim 3) test whether HSV- 1 worsens olfactory dysfunction in 5xFAD mice, accelerating the AD phenotype; specifically, we will test whether HSV-1-induced pathology and functional changes are diminished by optogenetic stimulation of mitral/tufted cells in the  frequency range and if entrainment of hippocampal  oscillations can prevent cellular and behavioral deficits elicited by HSV- 1. Understanding how viruses interact with the aging olfactory system, as well as with individuals who overexpress amyloidogenic peptides (FAD), to accelerate AD will identify potential biomarkers and therapies (e.g. vaccines or antiviral agents) that may slow or halt progression to clinical dementia, disability, and death. expression/pathways supportive of virus nfection in OE, OB, OT, entorhinal cortex, and biological fluids of FAD and sporadic AD (SAD) subjects; i

项目摘要：识别和治疗加速阿尔茨海默病(AD)的危险因素 对减缓疾病进展至关重要。甲型疱疹病毒(单纯疱疹病毒1型、水痘 带状疱疹病毒[VZV])是AD的潜在促进剂，因为它们增加了痴呆症的风险，并产生类似的 病理，包括淀粉样蛋白、神经炎症、神经变性和认知障碍1-3。在……里面 与文献平行，早期AD的特征是嗅觉丧失4，5，嗅觉上皮(OE)6，7， 和嗅觉感觉神经元(OSN)功能障碍(综述8)。因为嗅觉诱导伽马()振荡 在嗅球(OB)产生的是定向耦合到海马体9-12，嗅觉丧失会导致 海马区振荡减少，被认为会导致神经变性和认知 下降。14-16由于甲型疱疹病毒感染并在鼻腔内重新激活，甲型疱疹病毒破坏 嗅觉通路可能会加速AD。我们的初步数据显示：(1)与对照组相比，OB和嗅觉 家族性阿尔茨海默病(FAD)患者的肌束(OT)可上调病毒和炎症转录 (2)3例血清中2例检测到VZV即刻早期蛋白62 AD患者和0/4对照组；(3)HSV-1和VZV感染的人OE培养物(OEC)含有淀粉样蛋白和 鼻腔感染HSV-1的5xFAD小鼠OE淀粉样蛋白和 与未感染或接种前的对照组相比，嗅觉分别降低。总而言之，我们 假设甲型疱疹病毒感染OE参与了嗅觉内的病理过程 系统和海马体，从而加速疾病。为了检验这一假设，我们将：(目标1)确定 基因 海马体，(目标2)确定 人OE体外感染VZV和HSV-1是否会引起淀粉样蛋白的产生和 气味响应性丧失，重述AD的气味丧失；以及(目标3)测试HSV- 1加重5xFAD小鼠的嗅觉功能障碍，加速AD表型；具体地说，我们 将测试HSV-1诱导的病理和功能变化是否会被 频率范围内二尖瓣/簇生细胞的光遗传刺激 海马区振荡可预防单纯疱疹病毒所致的细胞和行为缺陷 1.了解病毒如何与老化的嗅觉系统以及与 过表达淀粉样多肽(FAD)，加速AD将识别潜在的生物标志物和治疗方法 (如疫苗或抗病毒药物)可能延缓或阻止进展为临床痴呆、残疾和死亡。 支持病毒感染的表达/通路在OE、OB、OT、内嗅皮层、 FAD和散发性AD(SAD)受试者的体液； 我