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

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.

CCR2 is localized in microglia and neurons, as well as infiltrating monocytes, in the lumbar spinal cord of ALS mice

“…Other studies reported that CCR2 is expressed in both infiltrating monocytes and microglia in a rodent model of traumatic brain injury [12]. Furthermore, another study reported CCR2 + monocyte infiltration in the perivascular areas of the primary motor cortex in ALS patients with TDP-43 pathology [13]. These data are discordant with the findings of Kawaguchi-Niida et al, who reported CCR2 expression exclusively in astrocytes [5].…”

Longitudinal biomarkers in amyotrophic lateral sclerosis

“…6,22 Activated astrocytes, microglia, and MCP1-CCR2-mediated infiltration of monocytes have been detected in the motor cortex of ALS patients and TDP-43 mouse models. 23 Lu et al demonstrated higher levels of creatine kinase, ferritin, TNF-a, and interleukins in plasma samples from PALS compared to controls, indicating that systemic inflammatory biomarkers acting on T-cell responses affected neuromuscular ALS pathology. 24 In addition, C-reactive protein (CRP), a general biomarker of inflammation, has been shown to be elevated in the serum of PALS and to correlate with more rapid disease progression.…”

Neuroimmunomodulatory and Neuroprotective Effects of the Flavonoid Apigenin in in vitro Models of Neuroinflammation Associated With Alzheimer’s Disease

“…Glial activation is a protective mechanism that regulates tissue repair in the early stage of neurodegeneration (Streit, 2005). However, excessive and prolonged activation contributes to a chronic neuroinflammatory response (Kraft and Harry, 2011), that might be involved in the onset and progression of most ND, such as Amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease (Heneka et al, 2015;Ghadery et al, 2017;Shi and Holtzman, 2018;Jara et al, 2019;McCauley and Baloh, 2019). According to van Horssen et al (2019), microglial and astrocytic activation leads to the production of inflammatory mediators such as cytokines, chemokines, reactive oxygen and nitrogen species, which eventually contribute to neuronal death.…”