权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

总结阿尔茨海默病（AD）是一个日益严重的健康问题，是世界上最常见的痴呆症类型。曾经是战俘的退伍军人在以后的生活中患痴呆症的风险增加了50%，在患创伤后应激障碍的退伍军人中，这一比例甚至更高。有证据表明，疾病和神经和神经系统疾病可以增加患骨质疏松症的风险，骨折的高发率。骨折，特别是髋关节骨折，死亡率，尤其是老年人。相反，骨质疏松症与痴呆症诊断风险增加有关。感觉。尽管有这些证据，痴呆症和骨质疏松症之间的直接联系，经常发生与衰老，从未被证实。有趣的是，一些基因突变是AD的危险因素，和骨质疏松症。例如，髓样细胞上表达的触发受体2（TREM 2）的突变在脑中的小胶质细胞和骨中的破骨细胞中表达，与AD和痴呆相关，并且与骨脆弱Landreth博士领导的最新研究表明，表达 R47 H TREM 2变体（TREM 2 R47 H/+小鼠）表现出TREM 2功能丧失和神经炎性营养不良。但负责TREM 2突变对骨量和强度影响的机制完全不清楚。在我们的初步研究结果表明，年龄为13个月的雌性TREM 2 R47 H/+小鼠表现出骨骼表型，型，皮质骨和松质骨质量和皮质骨生物力学性能降低。此外，本发明还提供了一种方法，女性，而不是男性，在1至12个月龄之间表现出降低的骨矿物质密度增加。工作其他研究表明，TREM 2-/-小鼠的低骨量归因于低破骨细胞β-连环蛋白激活，这表明在缺乏TREM 2功能的情况下有缺陷的典型Wnt信号传导。与这种可能性相一致，与WT小鼠相比，TREM 2 R47 H/+小鼠胫骨中Wnt靶基因细胞周期蛋白D1和Cx43的表达较低，而细胞周期蛋白D1和Cx43的表达较低。 D1、Lef 1和Axin 2的表达在来源于分离自以下的骨髓细胞的成骨细胞中降低： TREM 2 R47 H/+小鼠。另一方面，成骨细胞组成性β-连环蛋白激活或高骨密度的表达， mass（HMB）LRP 5突变体减少破骨细胞并增加小鼠的骨量。然而，细胞和Mo- TREM 2 R47 H/+小鼠中骨量和组成变化的理论机制仍然未知。此外，尚未测试低Wnt信号传导对TREM 2变体的骨骼效应的作用。基于我们的初步研究和已发表的证据表明，Wnt/β-catenin信号转导的减少是由于 TREM 2功能异常导致骨细胞骨吸收增加，并导致骨骼缺陷。科学为了验证这个假设，我们将1。调查TREM 2功能异常是否会导致雄性和雌性成年小鼠中性类固醇去除的顺序，2.确定骨小梁是否缺失 TREM 2足以引发在TREM 2 R47 H/+小鼠中观察到的骨骼表型，以及3.确定的作用 TREM 2缺陷导致骨表型中的骨细胞Wnt/β-连环蛋白信号传导。成功的com- 这些研究将拓宽我们对骨骼缺损的细胞和分子基础的理解对AD易感性增加的小鼠中。此外，它可能为改善这两种治疗方法奠定基础。 AD患者的认知和骨骼缺陷。