Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition
| Autor: | Donna M. Wilcock, Danielle Hawthorne, Tiffany L. Sudduth, Brittani R. Price, Sherika Johnson, Erica M. Weekman, Abigail E. Woolums |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Pathology medicine.medical_specialty Amyloid beta Immunology Hippocampus Mice Transgenic Plaque Amyloid Beta-amyloid lcsh:RC346-429 Antibodies Mice 03 medical and health sciences Cellular and Molecular Neuroscience Cognition 0302 clinical medicine Neuroinflammation TREM2 medicine Immuno-neurology Animals Receptors Immunologic Receptor lcsh:Neurology. Diseases of the nervous system Amyloid beta-Peptides Membrane Glycoproteins biology Microglia business.industry Research General Neuroscience Neurodegeneration medicine.disease 030104 developmental biology medicine.anatomical_structure Neurology biology.protein Systemic administration Immunotherapy business Alzheimer’s disease 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neuroinflammation Journal of Neuroinflammation, Vol 17, Iss 1, Pp 1-13 (2020) |
| ISSN: | 1742-2094 |
| DOI: | 10.1186/s12974-020-01915-0 |
| Popis: | BackgroundTriggering receptor expressed on myeloid cell-2 (TREM2) is a lipid and lipoprotein binding receptor expressed by cells of myeloid origin. Homozygous TREM2 mutations cause early onset progressive presenile dementia while heterozygous, point mutations triple the risk of Alzheimer’s disease (AD). Although human genetic findings support the notion that loss of TREM2 function exacerbates neurodegeneration, it is not clear whether activation of TREM2 in a disease state would result in therapeutic benefits. To determine the viability of TREM2 activation as a therapeutic strategy, we sought to characterize an agonistic Trem2 antibody (AL002a) and test its efficacy and mechanism of action in an aggressive mouse model of amyloid deposition.MethodsTo determine whether agonism of Trem2 results in therapeutic benefits, we designed both intracranial and systemic administration studies. 5XFAD mice in the intracranial administration study were assigned to one of two injection groups: AL002a, a Trem2-agonizing antibody, or MOPC, an isotype-matched control antibody. Mice were then subject to a single bilateral intracranial injection into the frontal cortex and hippocampus and euthanized 72 h later. The tissue from the left hemisphere was histologically examined for amyloid-beta and microglia activation, whereas the tissue from the right hemisphere was used for biochemical analyses. Similarly, mice in the systemic administration study were randomized to one of the aforementioned injection groups and the assigned antibody was administered intraperitoneally once a week for 14 weeks. Mice underwent behavioral assessment between the 12- and 14-week timepoints and were euthanized 24 h after their final injection. The tissue from the left hemisphere was used for histological analyses whereas the tissue from the right hemisphere was used for biochemical analyses.ResultsHere, we show that chronic activation of Trem2, in the 5XFAD mouse model of amyloid deposition, leads to reversal of the amyloid-associated gene expression signature, recruitment of microglia to plaques, decreased amyloid deposition, and improvement in spatial learning and novel object recognition memory.ConclusionsThese findings indicate that Trem2 activators may be effective for the treatment of AD and possibly other neurodegenerative disorders. |
| Databáze: | OpenAIRE |
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