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

• 批准号: 10259555
• 负责人: Lilian Irene Plotkin
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 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/10259555
• 关键词: Adult; Age-Months; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Arginine; Axon; Biomechanics; Bone Density; Bone Marrow Cells; Bone Matrix; Bone Resorption; Brain; Cell Count; Cells; Cognitive; Connexin 43; Cyclin D1; DNA Sequence Alteration; Data; Defect; Dementia; Dendrites; Deterioration; Diagnosis; Elderly; Excision; Exhibits; Female; Fracture; Gene Expression; Gene Proteins; Genes; Geometry; Goals; Gonadal Steroid Hormones; Health; 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; Structure; TREM2 gene; Testing; Tissues; Variant; Veterans; WNT Signaling Pathway; War; Woman; Work; aged; base; 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

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 阿尔茨海默氏病（AD）是日益严重的健康问题，是全球最常见的痴呆症类型。 曾经是战俘的退伍军人有50％以后发展痴呆症的风险，百分比为百分比 在发展后应激障碍的退伍军人中，这变得更高。证据表明心理 疾病，神经系统和神经系统疾病可能会增加发展骨质疏松症的风险 骨折的高患病率。骨折，特别是髋关节的骨折与增加有关 死亡率，尤其是在老年。相反，骨质疏松症与痴呆症的风险增加有关 NOSIS。尽管如此，所有这些证据还是痴呆症与骨质疏松症之间的直接联系，经常发生衰老， 从来没有得到结论。有趣的是，某些遗传突变是两个AD的危险因素 和骨质疏松症。例如，在髓样细胞2（trem2）上表达的触发受体的突变 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，骨 脆弱性。该应用程序顾问Landreth博士领导的最新研究表明，表达的小鼠 R47H TREM2变体（TREM2R47H/+小鼠）暴露于TREM2功能和神经性营养不良的损失。但是， 造成TREM2突变对骨骼质量和强度效应的机制尚不清楚。在 我们的初步发现，我们表明13个月大的女性Trem2r47h/+小鼠暴露了骨骼疾病 类型，具有改善的皮质和取消的骨骼和皮质骨生物力学特性。此外， 女性，但没有男性在1至12个月大的骨矿物质密度准确性降低。工作 其他人则表明，将trem2 - / - 小鼠中的低骨骼质量分配到低骨细胞β-catenin激活中，这表明 在没有TREM2功能的情况下，有缺陷的规范WNT信号传导。与这种可能性一致 与WT小鼠相比 D1，LEF1和AXIN2表达在源自从骨髓细胞中得出的破骨细胞中降低 TREM2R47H/+小鼠。另一方面，骨碎屑构成型β-catenin激活或高骨的表达 质量（HMB）LRP5突变体减少了小鼠的破骨细胞和骨骼量增加。然而，细胞和mo- Trem2R47H/+小鼠中骨骼质量变化和组成变化的内部机制尚不清楚。 此外，尚未测试低Wnt信号传导对TREM2变体骨骼效应的作用。基于 我们的初步研究和公开的证据我们提出，Wnt/β-catenin信号降低了 异常的TREM2功能导致整骨骨的分辨率增加，并导致骨骼缺陷 出现。为了检验这一假设，我们将1。 雄性和雌性小鼠中性别立体的清除查询，2。 TREM2足以引起在Trem2R47H/+小鼠中观察到的骨骼表型，3。 骨骼表型中的骨碎屑Wnt/β-catenin信号传导导致TREM2缺乏症。成功com- 这些研究的培养将扩大我们对骨骼缺陷的细胞和分子基础的理解 在具有增加易感性AD的小鼠中。此外，它可能为治疗改善两者的基础树立了基础 认知和骨骼定义了AD患者。