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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：
10408018
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/10408018
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 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 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

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