<p>Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of upper and lower motor neurons and pathological accumulation of TAR DNA-binding protein 43 (TDP-43). Microglial activation is a prominent feature of ALS pathology, and the receptor tyrosine kinase Axl, a marker of disease-associated microglia (DAM), has been proposed as a potential therapeutic target. Here, we investigated Axl signaling and its pharmacological inhibition in the inducible rNLS8 mouse model of ALS. Disease progression in the brain of these mice was accompanied by robust microgliosis, reflected by increased Iba1 Immunoreactivity in the hippocampus and by elevated Axl protein at later stages. Treatment with Bemcentinib (BGB), a selective Axl inhibitor, resulted in central nervous system penetration by the drug and evidence of target engagement as revealed by increased plasma soluble Axl and modulation of downstream signaling pathways in the brain, including reduced total Stat3 and Akt. Nevertheless, BGB administration failed to attenuate microglial or astrocytic reactivity in the brain and did not improve motor function, clasping behavior, or weight loss. In contrast, suppressed expression of the pathogenic TDP-43 cytoplasmic protein rapidly restored motor performance and body weight, confirming the reversibility of these phenotypes in the rNSL8 model. These data further establish Axl protein upregulation as a component of the microglial response in TDP-43-driven cortical neurodegeneration but suggest that Axl inhibition after BGB treatment was insufficient to counteract neuroinflammation or functional decline in the rNLS8 mouse model of ALS.</p>