TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy
Abstract Background Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer’s Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating ext...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2017-10-01
|
| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13024-017-0216-6 |
| _version_ | 1818300539570487296 |
|---|---|
| author | Shane M. Bemiller Tyler J. McCray Kevin Allan Shane V. Formica Guixiang Xu Gina Wilson Olga N. Kokiko-Cochran Samuel D. Crish Cristian A. Lasagna-Reeves Richard M. Ransohoff Gary E. Landreth Bruce T. Lamb |
| author_facet | Shane M. Bemiller Tyler J. McCray Kevin Allan Shane V. Formica Guixiang Xu Gina Wilson Olga N. Kokiko-Cochran Samuel D. Crish Cristian A. Lasagna-Reeves Richard M. Ransohoff Gary E. Landreth Bruce T. Lamb |
| author_sort | Shane M. Bemiller |
| collection | DOAJ |
| description | Abstract Background Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer’s Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular β-amyloid (Aβ) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular. Results Here we report that TREM2 deficiency leads to accelerated and exacerbated hyperphosphorylation and aggregation of tau in a humanized mouse model of tauopathy. TREM2 deficiency also results, indirectly, in dramatic widespread dysregulation of neuronal stress kinase pathways. Conclusions Our results suggest that deficiency of microglial TREM2 leads to heightened tau pathology coupled with widespread increases in activated neuronal stress kinases. These findings offer new insight into the complex, multiple roles of TREM2 in regulating Aβ and tau pathologies. |
| first_indexed | 2024-12-13T05:08:44Z |
| format | Article |
| id | doaj.art-d537fc31545b4db78783ea737d60c189 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-13T05:08:44Z |
| publishDate | 2017-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-d537fc31545b4db78783ea737d60c1892022-12-21T23:58:35ZengBMCMolecular Neurodegeneration1750-13262017-10-0112111210.1186/s13024-017-0216-6TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathyShane M. Bemiller0Tyler J. McCray1Kevin Allan2Shane V. Formica3Guixiang Xu4Gina Wilson5Olga N. Kokiko-Cochran6Samuel D. Crish7Cristian A. Lasagna-Reeves8Richard M. Ransohoff9Gary E. Landreth10Bruce T. Lamb11Department of Neurosciences, The Cleveland Clinic Lerner Research InstituteIndiana University School of Medicine Stark Neuroscience Research InstituteDepartment of Neurosciences, Case Western Reserve UniversityDepartment of Neurosciences, The Cleveland Clinic Lerner Research InstituteDepartment of Neurosciences, The Cleveland Clinic Lerner Research InstituteDepartment of Neurosciences, Northeastern Ohio Medical UniversityDepartment of Neurosciences, The Cleveland Clinic Lerner Research InstituteDepartment of Neurosciences, Northeastern Ohio Medical UniversityIndiana University School of Medicine Stark Neuroscience Research InstituteBiogen IDECIndiana University School of Medicine Stark Neuroscience Research InstituteDepartment of Neurosciences, The Cleveland Clinic Lerner Research InstituteAbstract Background Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer’s Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular β-amyloid (Aβ) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular. Results Here we report that TREM2 deficiency leads to accelerated and exacerbated hyperphosphorylation and aggregation of tau in a humanized mouse model of tauopathy. TREM2 deficiency also results, indirectly, in dramatic widespread dysregulation of neuronal stress kinase pathways. Conclusions Our results suggest that deficiency of microglial TREM2 leads to heightened tau pathology coupled with widespread increases in activated neuronal stress kinases. These findings offer new insight into the complex, multiple roles of TREM2 in regulating Aβ and tau pathologies.http://link.springer.com/article/10.1186/s13024-017-0216-6TREM2TauopathyAlzheimers diseaseInflammationImmunity |
| spellingShingle | Shane M. Bemiller Tyler J. McCray Kevin Allan Shane V. Formica Guixiang Xu Gina Wilson Olga N. Kokiko-Cochran Samuel D. Crish Cristian A. Lasagna-Reeves Richard M. Ransohoff Gary E. Landreth Bruce T. Lamb TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy Molecular Neurodegeneration TREM2 Tauopathy Alzheimers disease Inflammation Immunity |
| title | TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy |
| title_full | TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy |
| title_fullStr | TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy |
| title_full_unstemmed | TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy |
| title_short | TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy |
| title_sort | trem2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy |
| topic | TREM2 Tauopathy Alzheimers disease Inflammation Immunity |
| url | http://link.springer.com/article/10.1186/s13024-017-0216-6 |
| work_keys_str_mv | AT shanembemiller trem2deficiencyexacerbatestaupathologythroughdysregulatedkinasesignalinginamousemodeloftauopathy AT tylerjmccray trem2deficiencyexacerbatestaupathologythroughdysregulatedkinasesignalinginamousemodeloftauopathy AT kevinallan trem2deficiencyexacerbatestaupathologythroughdysregulatedkinasesignalinginamousemodeloftauopathy AT shanevformica trem2deficiencyexacerbatestaupathologythroughdysregulatedkinasesignalinginamousemodeloftauopathy AT guixiangxu trem2deficiencyexacerbatestaupathologythroughdysregulatedkinasesignalinginamousemodeloftauopathy AT ginawilson trem2deficiencyexacerbatestaupathologythroughdysregulatedkinasesignalinginamousemodeloftauopathy AT olgankokikocochran trem2deficiencyexacerbatestaupathologythroughdysregulatedkinasesignalinginamousemodeloftauopathy AT samueldcrish trem2deficiencyexacerbatestaupathologythroughdysregulatedkinasesignalinginamousemodeloftauopathy AT cristianalasagnareeves trem2deficiencyexacerbatestaupathologythroughdysregulatedkinasesignalinginamousemodeloftauopathy AT richardmransohoff trem2deficiencyexacerbatestaupathologythroughdysregulatedkinasesignalinginamousemodeloftauopathy AT garyelandreth trem2deficiencyexacerbatestaupathologythroughdysregulatedkinasesignalinginamousemodeloftauopathy AT brucetlamb trem2deficiencyexacerbatestaupathologythroughdysregulatedkinasesignalinginamousemodeloftauopathy |