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. 2020 Aug 14;17(1):238.
doi: 10.1186/s12974-020-01915-0.

Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition

Brittani R Price  1   2 , Tiffany L Sudduth  1 , Erica M Weekman  1   2 , Sherika Johnson  1 , Danielle Hawthorne  1 , Abigail Woolums  1   2 , Donna M Wilcock  3   4
Affiliations

Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition

Brittani R Price et al. J Neuroinflammation. .

Abstract

Background: Triggering 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.

Methods: To 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.

Results: Here, 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.

Conclusions: These findings indicate that Trem2 activators may be effective for the treatment of AD and possibly other neurodegenerative disorders.

Keywords: Alzheimer’s disease; Beta-amyloid; Immuno-neurology; Immunotherapy; Neuroinflammation; TREM2; Trem2.

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Conflict of interest statement

Dr. Wilcock has been a paid consultant of Alector. Data for Fig. 1 were generated by scientists at Alector.

Figures

Fig. 1
Fig. 1
AL002a promoted TREM2-dependent DAP12 and Syk phosphorylation. Panel a shows that AL002a binds to BMM derived from WT, but not Trem2 KO mice, as measured by FACS. A rat anti-Trem2 antibody from R&D Systems was used as a positive binding control and an isotype msIgG1 antibody as a negative control. Panel b: Following AL002a stimulation, WT or Trem2-/- BMM were lysed and immunoprecipitated with Trem2 antibody. Protein was loaded on a SDS gel in unreduced conditions. The membranes were first blotted with anti-phosphotyrosine antibody and later stripped and blotted again with anti-Dap12 antibody and anti-actin. Panel c: After AL002a stimulation, WT or TREM2-/- BMM were lysed and immunoprecipitated with Syk antibody. The membranes were first blotted with anti-phosphotyrosine antibody and later stripped and blotted again with anti-Syk antibody
Fig. 2
Fig. 2
Intracranial injection of AL002a activates microglia and ameliorates amyloid deposition in 5XFAD mice. Panel a shows the anti-mouse IgG immunohistochemistry in the frontal cortex and hippocampus of mice receiving intracranial injection of either control IgG or AL002a. Arrows indicate the exact injection site. Panel b shows the RT-PCR data obtained from the right hippocampus of the injected mice. All data are shown as a fold-change relative to the mean of the control antibody-injected mice. Data were analyzed using single, one-way ANOVA measures for each gene of interest, using a Bonferroni correction for multiple comparisons. Panel c shows the microglial activation (CD11b) in the hippocampus (images shown) and frontal cortex following intracranial injection of control antibody or AL002a. Panel d shows the total Aβ deposition in the hippocampus (images shown) and frontal cortex following intracranial injection of control antibody or AL002a. Panel e shows Congo red labeling of compact amyloid deposits in the hippocampus (images shown) and frontal cortex following intracranial injection of control antibody or AL002a. For all graphs, black bars represent AL002a while gray bars represent control antibody. *P < 0.05, **P < 0.01. For images in a–e, magnification = ×40, scale bars shown = 120 μm
Fig. 3
Fig. 3
Systemic administration of AL002a improves learning and memory and lowers amyloid deposition in 5XFAD mice. Panel a shows the radial-arm water maze data. Blocks 1–5 are day 1, and blocks 6–10 are day 2. The black line is the learning curve of the 5XFAD mice receiving AL002a, the gray line is the learning curve of the 5XFAD mice receiving control antibody, and the dashed line is the learning curve of the non-transgenic littermates receiving control or AL002a (data was pooled due to lack of difference between the two treatment groups). Panel b shows a bar graph to illustrate the difference in number of errors made for the final block of trials (block 10). Panel c shows the bar graph for the novel object recognition data, where % exploration time with novel object is shown. Fifty percent of the exploration time would represent chance. Panel d shows anti-mouse IgG immunohistochemistry from the frontal cortex and hippocampus of mice receiving either control or AL002a antibodies, magnification = ×200, scale bar = 25 μm. Panel e shows the total Aβ deposition in the hippocampus (images shown) and frontal cortex of control antibody or AL002a. Panel f shows Congo red labeling of compact amyloid deposits in the hippocampus (images shown) and frontal cortex of control antibody or AL002a. Panel g shows the biochemical assessment of soluble and insoluble beta-amyloid 38, 40, and 42 in the frontal cortex as measured using the Meso-Scale Discoveries multiplex ELISA. For all graphs, black bars are AL002a, and gray bars are control antibody. *P < 0.05, ** P < 0.01. For images in e and f, magnification = ×40, scale bars shown = 120 μm
Fig. 4
Fig. 4
Panel a shows RT-PCR data obtained from the right hippocampus. All data are shown as fold-change relative to the mean of the control antibody treated mice. Data were analyzed using single, one-way ANOVA measures for each gene of interest, using a Bonferroni correction for multiple comparisons. Panel b shows the microglial activation (CD11b) in the hippocampus (images shown) and frontal cortex of control antibody or AL002a. Magnification = 40×, scale bar shown = 120 μm. Panel c shows the microglial clustering around an amyloid plaque. Arrows highlight microglial cell bodies. Magnification = 400×, scale bar shown = 12.5 μm. For all graphs, black bars are AL002a, and gray bars are control antibody. *P < 0.05, **P < 0.01
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