Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy

Abstract

Though motor neurons (MNs) selectively degenerate in amyotrophic lateral sclerosis (ALS), other cell types are likely involved in this disease. We recently generated rNLS8 mice in which human TDP-43 (hTDP-43) pathology could be reversibly induced in neurons and expected microglia would contribute to neurodegeneration. However, only subtle microglial changes were detected during disease in the spinal cord, despite progressive MN loss, but microglia still reacted to inflammatory triggers in these mice. Notably, after the hTDP-43 expression was suppressed, microglia dramatically proliferated and changed their morphology and gene expression profiles. These abundant, reactive microglia selectively cleared neuronal hTDP-43. Finally, when microgliosis was blocked during the early recovery phase using PLX3397, a CSF1R/c-kit inhibitor, rNLS8 mice failed to regain full motor function, revealing an important neuroprotective role for microglia. Therefore, reactive microglia exert neuroprotective functions in this ALS model and definition of the underlying mechanism could point towards novel therapeutic strategies.

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…Furthermore, the administration of GW2580 (tyrosine kinase inhibitor) orally can regulate inflammation of both the CNS and peripheral nervous systems in the ALS animal model, attenuating motoneuronal cell death, slowing disease progression and extending life expectancy (Martinez‐Muriana et al, ). However, this has not been confirmed in other studies using different approaches to deplete microglia (Gowing et al, ; Spiller et al, ). A beneficial outcome of microglial depletion is also evident in neuropathic pain by reducing the expression of pro‐inflammatory cytokines (Lee, Shi, Fan, West, & Zhang, ), which was also confirmed in another study (Wang, Mao, Wu, & Wang, ).…”

The A1 astrocyte paradigm: New avenues for pharmacological intervention in neurodegeneration

“…Conversely, microglia clearly participate in the clearance of misfolded proteins and could have mainly adaptive roles in preclinical disease. They are also essential to CNS recovery in the aftermath of acute insults such as ischemia and experimental transactive response DNA binding protein 43 kDa proteinopathy . Therefore, rational therapeutic design will require a consideration of how microglial behaviors shift over the course of a chronic neurodegenerative disease, or even how to harness their most adaptive functionalities.…”

Interaction between microglia and retinal pigment epithelial cells determines the integrity of outer blood‐retinal barrier in diabetic retinopathy

“…In contrast to the normal physiological condition in which microglia displays ramified morphology, the pathological conditions activate microglia to transform to an amoeboid feature (Medana, Hunt, & Chan-Ling, 1997;Saijo & Glass, 2011). Although there is a consensus that reactive microglia played roles in brain and retinal diseases (Block, Zecca, & Hong, 2007; (Li, Eter, & Heiduschka, 2015;Saijo & Glass, 2011), it is also accepted that the nature of the microglial reaction varies according to the types of pathological conditions (Spiller et al, 2018). In the inner BRB disruption through vascular inflammation, microglia-derived interleukin (IL)-6 activates STAT3 in retinal endothelial cells (Yun et al, 2017).…”