Skeletal complications to a TREM2 variant associated with Alzheimer's Disease

与阿尔茨海默病相关的 TREM2 变异的骨骼并发症

基本信息

批准号：
10618952
负责人：
Lilian Irene Plotkin
金额：
--
依托单位：
RLR VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618952
关键词：
Adult Age Months Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Arginine Axon Biomechanics Bone Density Bone Marrow Cells Bone Matrix Bone Resorption Brain Cell Count Cell Separation Cells Cognitive Connexin 43 Cyclin D1 DNA Sequence Alteration Data Defect Dementia Dendrites Deterioration Diagnosis Elderly Excision Exhibits Female Fracture Gene Expression Genes Geometry Goals Gonadal Steroid Hormones Health Heterozygote High Prevalence Hip region structure Histidine Impairment In Vitro Individual LDL-Receptor Related Protein 1 Life Ligand Binding Link Measures Mental disorders Microglia Modeling Modulus Molecular Morphology Mus Mutant Strains Mice Mutation Myeloid Cells Neurologic Orchiectomy Osteoblasts Osteoclasts Osteocytes Osteoporosis Ovariectomy Patients Phenotype Post-Traumatic Stress Disorders Predisposition Prisoner Property Publishing Quality of life Reporting Risk Risk Factors Role Signal Transduction Skeletal system Skeleton Stress TREM2 gene Testing Tissues Variant Veterans WNT Signaling Pathway War Woman Work aged bcl-1 Genes beta catenin bone bone cell bone fragility bone loss bone mass bone quality bone strength cathepsin K cortical bone dementia risk genetic manipulation high risk improved in vivo insight lipoprotein receptor related protein 5 male men mortality mouse model mutant nervous system disorder prevent protein expression sex skeletal substantia spongiosa tibia

项目摘要

SUMMARY Alzheimer's disease (AD) is a growing health concern and is the most common type of dementia worldwide. Veterans who have been prisoners of war have a 50% greater risk to develop dementia later in life, a percentage that becomes even higher in veterans who develop posttraumatic stress disorder. Evidence indicates that mental illness and neurological and nervous system disorders can increase the risk of developing osteoporosis leading to high prevalence of bone fractures. Fractures, in particular of the hip, have been associated with increased mortality, especially in the elderly. Conversely, osteoporosis is associated with increased risk of dementia diag- nosis. In spite all this evidence, a direct link between dementia and osteoporosis, frequently occurring with aging, has never been conclusively demonstrated. Interestingly, some genetic mutations are risk factors for both AD and osteoporosis. As an example, mutations of the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is expressed in microglia in brain and in osteoclasts in bone correlate with AD and dementia, and with bone fragility. Recent studies led by Dr. Landreth, a Consultant in this application, showed that mice expressing the R47H TREM2 variant (TREM2R47H/+ mice) exhibit loss of TREM2 function and neuritic dystrophy. However, the mechanisms responsible for the TREM2 mutation effects on bone mass and strength are completely unclear. In our preliminary findings, we showed that aged 13-month-old female TREM2R47H/+ mice exhibit a skeletal pheno- type, with decreased cortical and cancellous bone mass and cortical bone biomechanical properties. In addition, female, but not male showed reduced bone mineral density accrual between 1 and 12 months of age. Work of others showed that low bone mass in TREM2-/- mice is ascribed to low osteoclast β-catenin activation, suggesting defective canonical Wnt signaling in the absence of TREM2 function. Consistent with this possibility, expression of Wnt target genes cyclin D1 and Cx43 in tibia is lower in TREM2R47H/+ compared to WT mice, whereas cyclin D1, Lef1 and Axin2 expression is reduced in osteoclastic cells derived from bone marrow cells isolated from TREM2R47H/+ mice. On the other hand, osteoclastic constitutive β-catenin activation or expression of a high bone mass (HMB) LRP5 mutant decreased osteoclasts and increased bone mass in mice. Yet, the cellular and mo- lecular mechanisms for the changes in the bone mass and composition in TREM2R47H/+ mice remain unknown. Further, the role of low Wnt signaling on the skeletal effect of the TREM2 variant has not been tested. Based on our preliminary studies and on published evidence we propose that reduced Wnt/β-catenin signaling due to abnormal TREM2 function leads to increased osteoclastic bone resorption and results in skeletal defi- ciencies. To test this hypothesis we will 1. Investigate whether abnormal TREM2 function worsens the conse- quences of sex steroid removal in male and female adult mice, 2. Determine whether deletion of osteoclastic TREM2 is sufficient to elicit the skeletal phenotype observed in TREM2R47H/+ mice, and 3. Determine the role of osteoclastic Wnt/β-catenin signaling in the bone phenotype resulting from TREM2 deficiency. Successful com- pletion of these studies will widen our understanding of the cellular and molecular basis of the skeletal defects in mice with increased susceptibility to develop AD. Further, it might set the basis for treatments to improve both the cognitive and skeletal deficits in AD patients.

概括阿尔茨海默病 (AD) 是一个日益严重的健康问题，也是全世界最常见的痴呆症类型。成为战俘的退伍军人在以后的生活中患痴呆症的风险增加 50% 有证据表明，患有创伤后应激障碍的退伍军人的这一比例甚至更高。疾病以及神经和神经系统疾病会增加患骨质疏松症的风险骨折（尤其是髋部骨折）的高发生率与骨折的增加有关。死亡率，尤其是老年人的死亡率，骨质疏松症与痴呆症诊断风险增加有关。尽管有所有这些证据，但痴呆症和骨质疏松症之间存在直接联系，并且经常随着年龄的增长而发生。统计数据尚未最终证明，某些基因突变是 AD 的危险因素。例如，骨髓细胞 2 上表达的触发受体 (TREM2) 的突变。在大脑中的小胶质细胞和骨骼中的破骨细胞中表达，与 AD 和痴呆相关，并且与骨骼相关该应用的顾问 Landreth 博士最近领导的研究表明，小鼠表达 R47H TREM2 变异体（TREM2R47H/+ 小鼠）表现出 TREM2 功能丧失和神经性营养不良。 TREM2 突变对骨量和强度影响的机制尚不清楚。我们的初步研究结果表明，13 个月大的雌性 TREM2R47H/+ 小鼠表现出骨骼现象类型，皮质骨和松质骨量以及皮质骨生物力学特性降低。女性（而非男性）在 1 至 12 个月大时表现出骨矿物质密度减少。其他人表明，TREM2-/- 小鼠的低骨量归因于破骨细胞 β-连环蛋白激活率低，这表明在缺乏 TREM2 功能的情况下，经典 Wnt 信号传导有缺陷，这与这种可能性一致。与 WT 小鼠相比，TREM2R47H/+ 胫骨中 Wnt 靶基因 cyclin D1 和 Cx43 的含量较低，而 cyclin 源自骨髓细胞的破骨细胞中 D1、Lef1 和 Axin2 表达降低另一方面，破骨细胞的β-连环蛋白激活或骨表达高。 Mass (HMB) LRP5 突变体减少了小鼠的破骨细胞并增加了骨量。 TREM2R47H/+ 小鼠骨量和骨成分变化的分子机制仍不清楚。此外，低 Wnt 信号传导对 TREM2 变体骨骼效应的作用尚未得到测试。我们的初步研究和已发表的证据表明，Wnt/β-连环蛋白信号传导的减少是由于 TREM2 功能异常导致破骨细胞骨吸收增加并导致骨骼缺陷为了验证这一假设，我们将 1. 研究 TREM2 功能异常是否会导致结果恶化。雄性和雌性成年小鼠中性类固醇去除的序列，2.确定破骨细胞是否缺失 TREM2 足以引发在 TREM2R47H/+ 小鼠中观察到的骨骼表型，并且 3. 确定 TREM2 缺陷导致的骨表型中破骨细胞 Wnt/β-catenin 信号传导成功。这些研究的完成将扩大我们对骨骼缺陷的细胞和分子基础的理解此外，它可能为改善这两种情况的治疗奠定基础。 AD 患者的认知和骨骼缺陷。