Inhibition of discoidin domain receptor (DDR)-1 with nilotinib alters CSF miRNAs and is associated with reduced inflammation and vascular fibrosis in Alzheimer's Disease

Discoidin Domain Receptor (DDR)-1 is activated by collagen. Nilotinib is a tyrosine kinase inhibitor that is FDAapproved for leukemia and potently inhibits DDR-1. Individuals diagnosed with mild–moderate Alzheimer’s disease (AD) treated with nilotinib (versus placebo) for 12 months showed reduction of amyloid plaque and cerebrospinal fluid (CSF) amyloid, and attenuation of hippocampal volume loss. However, the mechanisms are unclear. Here, we explored unbiased next generation whole genome miRNA sequencing from AD patients CSF miRNAs were matched with their corresponding mRNAs using gene ontology. Changes in CSF miRNAs were confirmed via measurement of CSF DDR1 activity and plasma levels of AD biomarkers. Approximately 1050 miRNAs are detected in the CSF but only 17 miRNAs are specifically altered between baseline and 12-month treatment with nilotinib versus placebo.