MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology

Javier H Jara,Edward F Xie,Nuran Kocak,P Hande Özdinler,Qinwen Mao,Eileen H Bigio,Mukesh Gautam

doi:10.1186/s12974-019-1589-y

Abstract

BackgroundThe involvement of non-neuronal cells and the cells of innate immunity has been attributed to the initiation and progression of ALS. TDP-43 pathology is observed in a broad spectrum of ALS cases and is one of the most commonly shared pathologies. The potential involvement of the neuroimmune axis in the motor cortex of ALS patients with TDP-43 pathology needs to be revealed. This information is vital for building effective treatment strategies.MethodsWe investigated the presence of astrogliosis and microgliosis in the motor cortex of ALS patients with TDP-43 pathology. prpTDP-43A315T-UeGFP mice, corticospinal motor neuron (CSMN) reporter line with TDP-43 pathology, are utilized to reveal the timing and extent of neuroimmune interactions and the involvement of non-neuronal cells to neurodegeneration. Electron microscopy and immunolabeling techniques are used to mark and monitor cells of interest.ResultsWe detected both activated astrocytes and microglia, especially rod-like microglia, in the motor cortex of patients and TDP-43 mouse model. Besides, CCR2+ TMEM119- infiltrating monocytes were detected as they penetrate the brain parenchyma. Interestingly, Betz cells, which normally do not express MCP1, were marked with high levels of MCP1 expression when diseased.ConclusionsThere is an early contribution of a neuroinflammatory response for upper motor neuron (UMN) degeneration with respect to TDP-43 pathology, and MCP1-CCR2 signaling is important for the recognition of diseased upper motor neurons by infiltrating monocytes. The findings are conserved among species and are observed in both ALS and ALS-FTLD patients.

Highlights

The involvement of non-neuronal cells and the cells of innate immunity has been attributed to the initiation and progression of Amyotrophic lateral sclerosis (ALS)
Evidence of microgliosis around Betz cells in ALS with TDP-43 pathology To investigate the role of neuroinflammation with respect to ALS with TDP-43 pathology, we first investigated the presence of microgliosis and astrogliosis in the primary motor cortex Brodmann area 4 of normal controls, ALS cases, and ALS-FTLD cases with TDP-43 pathology (Fig. 1A’, A”; Table 1)
The total number of microglia were comparable between normal controls (36 ± 1, n = 3) and ALS cases (36 ± 2, n = 9; p = 0.786); there was a significant decrease of quiescent microglia in ALS patients with TDP-43 pathology and about 21% increase of activated microglia in ALS patients with TDP-43 pathology

Summary

Introduction

The potential involvement of the neuroimmune axis in the motor cortex of ALS patients with TDP-43 pathology needs to be revealed. This information is vital for building effective treatment strategies. Astrogliosis and innate immune response of tissueresident microglia has been described in patients and mouse models of ALS [6,7,8,9] These studies focused mostly on the spinal cord. Our previous analyses revealed the presence of microgliosis in the diseased motor cortex and interaction of activated microglia with degenerating Betz cells of familial and sporadic ALS patients [10], findings recapitulated in the motor cortex of hSOD1G93A mice [11, 12]

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