Pinpointing Brain TREM2 Levels in Two Mouse Models of Alzheimer\u2019s Disease

Silvio R Meier,Dag Sehlin,Stina Syvänen,Greta Hultqvist

doi:10.1007/s11307-021-01591-3

Abstract

PurposeThe triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by brain microglia. Microglial activation, as observed in Alzheimer’s disease (AD) as well as in transgenic mice expressing human amyloid-beta, appears to increase soluble TREM2 (sTREM2) levels in CSF and brain. In this study, we used two different transgenic mouse models of AD pathology and investigated the potential of TREM2 to serve as an in vivo biomarker for microglial activation in AD.ProceduresWe designed and generated a bispecific antibody based on the TREM2-specific monoclonal antibody mAb1729, fused to a single-chain variable fragment of the transferrin receptor binding antibody 8D3. The 8D3-moiety enabled transcytosis of the whole bispecific antibody across the blood-brain barrier. The bispecific antibody was radiolabeled with I-125 (ex vivo) or I-124 (PET) and administered to transgenic AD and wild-type (WT) control mice. Radioligand retention in the brain of transgenic animals was compared to WT mice by isolation of brain tissue at 24 h or 72 h, or with in vivo PET at 24 h, 48 h, and 72 h. Intrabrain distribution of radiolabeled mAb1729-scFv8D3CL was further studied by autoradiography, while ELISA was used to determine TREM2 brain concentrations.ResultsTransgenic animals displayed higher total exposure, calculated as the AUC based on SUV determined at 24h, 48h, and 72h post injection, of PET radioligand [124I]mAb1729-scFv8D3CL than WT mice. However, differences were not evident in single time point PET images or SUVs. Ex vivo autoradiography confirmed higher radioligand concentrations in cortex and thalamus in transgenic mice compared to WT, and TREM2 levels in brain homogenates were considerably higher in transgenic mice compared to WT.ConclusionAntibody-based radioligands, engineered to enter the brain, may serve as PET radioligands to follow changes of TREM2 in vivo, but antibody formats with faster systemic clearance to increase the specific signal in relation to that from blood in combination with antibodies showing higher affinity for TREM2 must be developed to further progress this technique for in vivo use.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia
triggering receptor expressed on myeloid cells 2 (TREM2) Levels Increase with Age soluble part of TREM2 (sTREM2) and Aβ protofibril concentrations were determined in the Tris-buffered saline (TBS) soluble fraction of homogenates prepared from brains isolated from ArcSwe mice of different ages: 6–7, 10, 13, 16, 18, and 20 months (Fig. 2a–b). sTREM2 levels increased with age and correlated closely with Aβ protofibrils (Fig. 2c)
Brain tissue isolated from ArcSwe mice that had received the anti-Aβ drug NB360 [31] (BACE-1 inhibitor) with confirmed reduction of Aβ pathology [27] displayed reduced sTREM2 brain concentrations compared to littermates that did not receive NB360

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia. The number of people suffering from AD isMeier S.R. et al.: Pinpointing Brain TREM2 Levels expected to increase, mainly due to an older population worldwide as age is the key risk factor for the disease [1]. Microglial activation, measured with [18F]GE180, was reported already at an early age when Aβ deposition was sparse and only detectable by sensitive histological methods but not with [18F]florbetaben PET This indicates that sTREM2 might serve as a biomarker for microglial activation at a very early disease stage, and it would be beneficial to image and quantify sTREM2 concentrations in vivo with PET imaging. This approach could be an alternative to TSPO PET radioligands that suffer from many challenges such low brain distribution, unspecific and genotype-dependent binding

Objectives

Methods

Results

Conclusion