Abstract
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.
Highlights
Triggering receptor expressed on myeloid cell-2 (TREM2) is a lipid and lipoprotein binding receptor expressed by cells of myeloid origin
While inflammation has long been understood to be a part of the brain response to plaque and tangle pathology associated with Alzheimer’s disease (AD), the recent identification of mutations in the triggering receptor expressed on myeloid cell-2 (TREM2), a single transmembrane receptor expressed on the surface of microglia, has provoked further excitement surrounding immune modulation as a candidate therapeutic target for AD [5, 6]
Trem2 signaling with AL002a AL002a is a mouse IgG1 antibody that has been generated to recognize the extracellular portion of the TREM2 receptor
Summary
Triggering receptor expressed on myeloid cell-2 (TREM2) is a lipid and lipoprotein binding receptor expressed by cells of myeloid origin. To date, targeting the beta-amyloid (Aβ) peptide within amyloid plaques remains a leading candidate for therapeutic targeting; efforts have been hampered by lack of efficacy and/or significant adverse events [2,3,4]. While inflammation has long been understood to be a part of the brain response to plaque and tangle pathology associated with AD, the recent identification of mutations in the triggering receptor expressed on myeloid cell-2 (TREM2), a single transmembrane receptor expressed on the surface of microglia, has provoked further excitement surrounding immune modulation as a candidate therapeutic target for AD [5, 6]. The resulting changes in gene expression alongside post-transcriptional modifications induce an increased cellular response to colony-stimulating factor [13], actin reorganization [11], process extension [14], cytokine release [15, 16], survival [17, 18], proliferation [13], migration [19], and phagocytosis [20] in Trem expressing dendritic cells (DC) [16], tissue macrophages [21], osteoclasts [22], and microglia [23]
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