Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α‐secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α‐secretase‐mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho‐SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β‐peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9‐bound. Moreover, in a mouse model for Alzheimer's disease‐related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease‐associated state.
Highlights
Alzheimer’s disease (AD) and related disorders are devastating diseases threatening our aging society, and still, no cure is available
4D9, a rat IgG2a antibody, was selected for additional studies based on its ability to significantly enhance cell membrane triggering receptor expressed on myeloid cells 2 (TREM2) levels and to reduce soluble TREM2 (sTREM2) levels similar to an ADAM protease inhibitor (Fig 1B and C)
Microgliosis is observed in numerous neurological disorders, and only recently evidence has been presented that TREM2-dependent microglial functions appear to be protective in AD models (Ulland et al, 2017; Focke et al, 2019; Parhizkar et al, 2019), AD patients
Summary
Alzheimer’s disease (AD) and related disorders are devastating diseases threatening our aging society, and still, no cure is available. Since a number of recent clinical trials using amyloid b-peptide (Ab)based therapeutic approaches failed to improve cognition or even worsened the clinical outcome of patients (Egan et al, 2019), novel targets are desperately needed. It appears that anti-Ab therapeutics may have to be administered decades before symptom onset, since at the time patients are enrolled in clinical studies they are amyloid positron emission tomography (PET)-positive (Sevigny et al, 2016) even if they have not yet developed overt dementia.
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