Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease.
Alzheimer Disease/etiology/*metabolism/pathology; Alzheimer's disease; Amyloid beta-Peptides/*metabolism; Animal; Animal/physiology; Animals; Behavior; Blotting; Brain Injuries; Brain/*metabolism/pathology; Disease Models; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Immunohistochemistry; Inbred C57BL; Inflammation/*metabolism/pathology; macrophage; Mice; neuroinflammation; Transgenic; traumatic brain injury; Traumatic/complications/*metabolism/*pathology; Western
Traumatic brain injury (TBI) has acute and chronic sequelae, including an increased risk for the development of Alzheimer's disease (AD). TBI-associated neuroinflammation is characterized by activation of brain-resident microglia and infiltration of monocytes; however, recent studies have implicated beta-amyloid as a major manipulator of the inflammatory response. To examine neuroinflammation after TBI and development of AD-like features, these studies examined the effects of TBI in the presence and absence of beta-amyloid. The R1.40 mouse model of cerebral amyloidosis was used, with a focus on time points well before robust AD pathologies. Unexpectedly, in R1.40 mice, the acute neuroinflammatory response to TBI was strikingly muted, with reduced numbers of CNS myeloid cells acquiring a macrophage phenotype and decreased expression of inflammatory cytokines. At chronic time points, macrophage activation substantially declined in non-Tg TBI mice; however, it was relatively unchanged in R1.40 TBI mice. The persistent inflammatory response coincided with significant tissue loss between 3 and 120 days post-injury in R1.40 TBI mice, which was not observed in non-Tg TBI mice. Surprisingly, inflammatory cytokine expression was enhanced in R1.40 mice compared with non-Tg mice, regardless of injury group. Although R1.40 TBI mice demonstrated task-specific deficits in cognition, overall functional recovery was similar to non-Tg TBI mice. These findings suggest that accumulating beta-amyloid leads to an altered post-injury macrophage response at acute and chronic time points. Together, these studies emphasize the role of post-injury neuroinflammation in regulating long-term sequelae after TBI and also support recent studies implicating beta-amyloid as an immunomodulator.
Kokiko-Cochran Olga N; Ransohoff Lena; Veenstra Mike; Lee Sungho; Saber Maha; Sikora Matt; Teknipp Ryan; Xu Guixiang; Bemiller Shane M; Wilson Gina; Crish Samuel; Bhaskar Kiran; Lee Yu-Shang; Ransohoff Richard M; Lamb Bruce T
Journal of neurotrauma
2016
2016-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1089/neu.2015.3970" target="_blank" rel="noreferrer noopener">10.1089/neu.2015.3970</a>
TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy.
*Alzheimers disease; *Immunity; *Inflammation; *Tauopathy; *TREM2; Animal; Animals; Disease Models; Humans; Immunologic/*deficiency; Inbred C57BL; Membrane Glycoproteins/*deficiency; Mice; Microglia/metabolism; Protein Kinases/*metabolism; Receptors; Signal Transduction/physiology; tau Proteins/*metabolism; Tauopathies/metabolism/*pathology; Transgenic
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 beta-amyloid (Abeta) 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 Abeta and tau pathologies.
Bemiller Shane M; McCray Tyler J; Allan Kevin; Formica Shane V; Xu Guixiang; Wilson Gina; Kokiko-Cochran Olga N; Crish Samuel D; Lasagna-Reeves Cristian A; Ransohoff Richard M; Landreth Gary E; Lamb Bruce T
Molecular neurodegeneration
2017
2017-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s13024-017-0216-6" target="_blank" rel="noreferrer noopener">10.1186/s13024-017-0216-6</a>