Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the presence of phosphorylated tau neurofibrillary tangles and extracellular deposits of amyloid beta plaques (Aβ) in the brain. Microglia cells have been proposed to be involved in amyloid plaque formation since activated microglia produce inflammatory cytokines that contribute to a hostile neuronal environment, exacerbating AD pathogenesis.

Results: In the present work, we have used the pharmacological Axl inhibitor BGB, to evaluate the therapeutic potential of targeting Axl signaling in 5xFAD mice. We have evaluated the effect of Axl inhibition measuring changes in total Axl levels and its soluble fragment (sAxl) across the hippocampus, plasma, and CSF of 5xFAD mice and WT mice. As expected, we found a significant upregulation of Aβ plaques and microglia in 5xFAD mice, and interestingly a concomitant upregulation of Axl levels in the hippocampus of 5xFAD mice. We observed, although not statistically significant, a trend of increasing levels of sAxl in CSF and plasma of mice receiving BGB. Unfortunately, no significant effect of BGB drug was detected in 5xFAD mice when Aβ-plaque burden and Iba1 immunoreactivity was measured after the treatment.

Conclusion: Overall, the preliminary findings do not show a significant effect of Axl inhibitor BGB in the brain. The reduced BBB penetrance of the drug could be a potential explanation for lack of significant changes in Axl levels and microglia activation. Further studies increasing dosing time and cohort size could potentially improve the outcome.