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.

摘要阿尔茨海默病(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。曾当过战俘的退伍军人在晚年患痴呆症的风险要高出50%，在患有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，精神疾病疾病以及神经系统和神经系统疾病会增加罹患骨质疏松症的风险骨折的高发生率。骨折，特别是髋部骨折，与增加的死亡率，特别是在老年人中。相反，骨质疏松症与痴呆症诊断风险的增加有关诺西斯。尽管有所有这些证据，痴呆症和骨质疏松症之间的直接联系经常随着年龄的增长而发生，从未被确凿地证明过。有趣的是，一些基因突变是两种AD的危险因素骨质疏松症。例如，表达在髓样细胞2(TREM2)上的触发受体的突变在脑内的小胶质细胞和在骨中的破骨细胞中表达，与AD和痴呆以及与骨相关脆弱。兰德雷思博士是这一应用程序的顾问，他最近领导的研究表明，表达该基因的小鼠 R47H TREM2变异体(TREM2R47H/+小鼠)表现出TREM2功能丧失和神经性营养不良。然而， TREM2突变对骨量和强度影响的机制完全不清楚。在……里面我们的初步发现表明，13个月大的雌性TREM2R47H/+小鼠表现出骨骼表型。类型，皮质骨和松质骨量及皮质骨生物力学性能降低。此外, 女性，而不是男性，在1到12个月龄之间表现出骨密度增加的减少。的工作其他研究表明，TREM2-/-小鼠的低骨量归因于破骨细胞β-连环蛋白的低激活，这表明在缺乏TREM2功能的情况下存在典型的Wnt信号缺陷。与这种可能性相一致的，表达与WT小鼠相比，TREM2R47H/+小鼠胫骨中WNT靶基因Cyclin D1和Cx43的表达水平较低，而Cyclin 破骨细胞来源的破骨细胞中D1、Lef1和Axin2表达降低 TREM2R47H/+小鼠。另一方面，破骨细胞结构性β-连环蛋白的激活或表达水平较高 MASS(HMB)LRP5突变体使小鼠破骨细胞减少，骨量增加。然而，细胞和分子- TREM2R47H/+小鼠骨量和成分变化的机制尚不清楚。此外，低Wnt信号在TREM2变体的骨骼效应中的作用尚未得到测试。基于我们的初步研究和已发表的证据表明，Wnt/β-catenin信号转导减少是由于 TREM2功能异常导致破骨细胞性骨吸收增加，导致骨缺如。紧急情况。为了验证这一假设，我们将1.调查TREM2功能异常是否会恶化结论- 雄性和雌性成年小鼠性类固醇去除的顺序，2.确定破骨细胞的缺失 TREM2足以诱导在TREM2R47H/+小鼠中观察到的骨骼表型，以及3.确定TREM2的作用破骨细胞WnT/β-连环蛋白信号在TREM2缺乏引起的骨表型中的作用。成功的COM- 这些研究的完善将扩大我们对骨骼缺陷的细胞和分子基础的理解易患阿尔茨海默病的小鼠。此外，它可能会为改善这两种情况的治疗奠定基础阿尔茨海默病患者的认知和骨骼功能障碍。