Acceleration of Alzheimer’s Disease Pathology Due to Osteoarthritis-Associated Inflammation

骨关节炎相关炎症加速阿尔茨海默病的病理变化

• 批准号: 10292125
• 负责人: Blaine A. Christiansen
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292125
• 关键词: APP-PS1; Acceleration; Affect; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; American; Amyloid Proteins; Amyloid beta-Protein; Behavior; Behavioral; Biomechanics; Bone Spur; Brain; Cognitive; Cognitive deficits; Data; Degenerative polyarthritis; Dementia; Deterioration; Diagnostic; Disease; Disease Progression; Economics; Elderly; Funding; Future; Genetic; Goals; Grant; Health; Hindlimb Suspension; Human Amyloid Precursor Protein; Impaired cognition; Inflammation; Inflammatory; Injury; Intervention; Investigation; Joints; Knee Injuries; Knee joint; Lead; Link; Mechanics; Metabolism; Modeling; Mus; Neurons; Organ; Parents; Peptide Hydrolases; Peripheral; Pharmacologic Substance; Phase; Play; Population; Presenile Alzheimer Dementia; Process; Quality of life; Research; Risk; Role; Senile Plaques; Synovial Membrane; Synovial joint; Synovitis; Testing; Time; Transgenic Mice; Transgenic Organisms; Translational Research; Wild Type Mouse; Woman; abeta accumulation; abeta deposition; abnormally phosphorylated tau; aged; anterior cruciate ligament injury; anterior cruciate ligament rupture; base; clinically relevant; cognitive function; early onset; human old age (65+); insight; joint destruction; joint inflammation; joint injury; joint loading; men; mouse model; mutant; novel; novel therapeutic intervention; older patient; parent grant; presenilin-1; preservation; prevent; slow potential; systemic inflammatory response; tau Proteins; therapeutic development; translational study

Project Summary/Abstract: Alzheimer’s Disease (AD) and osteoarthritis (OA) are two of the most common health conditions affecting the elderly population, and the economic and health impacts of AD and OA will markedly increase over the next several decades as the elderly population grows. Deposition of beta-amyloid protein (Aβ) outside neurons and abnormally phosphorylated Tau protein (pTau) inside neurons are two hallmark changes in the brain associated with AD. Interestingly, our preliminary studies also found Aβ deposition and higher levels of pTau in the joints of aged mice (96-weeks-old) and during OA progression in mouse knee joints following non-invasive ACL injury. Additionally, we found that 17-month-old APP/PS1 mice, an established model of AD, had Aβ plaques in the synovium of their knee joints. Taken together, these observations suggest a common underlying mechanism between OA and AD, and raise the possibility that systemic inflammation associated with OA may accelerate the progression of AD. The overall goal of our funded R01 grant is to determine how biomechanical interventions can be utilized following joint injury to mitigate joint inflammation and affect the progression of post-traumatic osteoarthritis (PTOA). The research proposed in this supplement will extend this line of investigation to determine if systemic inflammation during OA progression accelerates AD progression in a genetic mouse model of AD (APP/PS1 mice), and whether this effect can be mitigated by joint unloading during the early phase post-injury. We hypothesize that OA and AD share a similar pathogenetic mechanism, and that inflammation associated with OA progression can accelerate AD progression and cognitive decline. Our specific aim is to determine whether OA-associated systemic inflammation accelerates the onset of AD progression and deterioration of cognitive function in APP/PS1 mice, and whether this acceleration can be mitigated by early phase unloading. This supplement extends the focus of our research to investigate the connection between OA and AD pathologies in the joint and brain. This supplement study will lead to future R01 applications that will expand these results into more comprehensive translational research on whether systemic inflammation from the peripheral organs such as synovial joints may be associated with early-onset and faster progression of AD. It is also our long-term goal to develop early diagnostic strategies and novel pharmaceutical interventions to prevent the accumulation of Aβ and pTau in the joint and brain, which could potentially slow or prevent the progression of both OA and AD.

项目概要/摘要： 阿尔茨海默氏病（AD）和骨关节炎（OA）是两种最常见的影响老年人的健康状况。 老年人口，AD和OA的经济和健康影响将在未来显著增加 几十年来，随着老年人口的增长。β-淀粉样蛋白（Aβ）在神经元外沉积， 神经元内异常磷酸化的Tau蛋白（pTau）是大脑中与神经元相关的两个标志性变化。 与AD。有趣的是，我们的初步研究还发现Aβ沉积和高水平的pTau在关节中， 老年小鼠（96周龄）和非侵入性ACL损伤后小鼠膝关节OA进展期间。 此外，我们发现，17个月大的APP/PS1小鼠，一种已建立的AD模型，在大脑中动脉中有Aβ斑块。 膝关节的滑膜综合起来，这些观察结果表明了一个共同的潜在机制 OA和AD之间的关系，并增加了与OA相关的全身炎症可能加速的可能性。 AD的进展。我们资助的R 01赠款的总体目标是确定生物力学干预如何 可以在关节损伤后使用，以减轻关节炎症并影响创伤后炎症的进展。 骨关节炎（PTOA）。本补充报告中提出的研究将扩展这一调查路线，以确定 如果OA进展期间的全身炎症加速AD遗传小鼠模型中的AD进展， (APP/PS1小鼠），以及这种影响是否可以通过在损伤后早期阶段的关节去负荷来减轻。 我们假设OA和AD有相似的发病机制， OA进展可加速AD进展和认知能力下降。我们的具体目标是确定 OA相关的全身性炎症加速了AD的发生和认知功能的恶化。 APP/PS1小鼠的功能，以及这种加速是否可以通过早期卸载来缓解。这 补充扩展了我们的研究重点，以调查OA和AD病理之间的联系， 关节和大脑。这项补充研究将导致未来的R 01应用，将这些结果扩展到 更全面的转化研究是否来自外周器官的全身性炎症， 因为滑液关节可能与AD的早发性和更快进展有关。也是我们的长期目标 开发早期诊断策略和新的药物干预措施，以防止Aβ的积累 以及关节和大脑中的pTau，这可能潜在地减缓或预防OA和AD的进展。