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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目摘要/摘要：阿尔茨海默氏病 (AD) 和骨关节炎 (OA) 是影响人类健康的两种最常见的健康状况人口老龄化，AD 和 OA 对经济和健康的影响将在未来显着增加几十年来，随着老年人口的增长，β-淀粉样蛋白（Aβ）在神经元外沉积，并且神经元内异常磷酸化的 Tau 蛋白 (pTau) 是大脑相关的两个标志性变化暗示性地，我们的初步研究还发现 Aβ 沉积和关节中更高水平的 pTau。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）的大脑皮层中存在 Aβ 斑块。综上所述，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，并提出了与 OA 相关的全身炎症可能加速的可能性我们资助的 R01 拨款的总体目标是确定如何进行生物力学干预。可在关节损伤后使用，以减轻关节炎症并影响创伤后的进展本补充材料中提出的研究将扩展这一研究范围以确定骨关节炎（PTOA）。如果 OA 进展期间的全身炎症会加速 AD 遗传小鼠模型中的 AD 进展（APP/PS1 小鼠），以及是否可以通过损伤后早期的关节卸载来减轻这种影响。我们认为 OA 和 AD 具有相似的致病机制，并且炎症与我们的具体目标是确定 OA 的进展是否会加速 AD 的进展和认知能力的下降。 OA相关全身炎症加速AD进展和认知能力恶化 APP/PS1 小鼠中的功能，以及是否可以通过早期卸载来减轻这种加速。补充品扩展了我们研究的重点，以调查 OA 和 AD 病理之间的联系这项补充研究将导致未来的 R01 应用，将这些结果扩展到关于系统性炎症是否来自外周器官（例如因为滑膜关节可能与 AD 的早发和更快进展有关，这也是我们的长期目标。制定早期诊断策略和新型药物干预措施以防止 Aβ 积累 pTau 存在于关节和大脑中，可能会减缓或阻止 OA 和 AD 的进展。