Inhibition of discoidin domain receptor (DDR)-1 with nilotinib induces autophagy and reduces inflammation and vascular fibrosis in Alzheimer’s disease

Abstract

Abstract Discoidin Domain Receptor (DDR)-1 is activated by collagen. Nilotinib is a tyrosine kinase inhibitor that is FDA-approved 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 dopamine catabolism and hippocampal volume loss. Unbiased next generation whole genome miRNA sequencing from CSF of AD patients was performed and miRNAs were matched with their corresponding mRNAs using gene ontology. Changes in CSF miRNAs were confirmed via measurement of CSF DDR1 activity, plasma levels of AD biomarkers, and breeding DDR1 knockout mice with a transgenic model of CNS vascular amyloidosis. Approximately 1050 miRNAs are detected in the CSF but only 17 miRNAs are specifically altered between baseline and 12-months treatment with nilotinib versus placebo. Treatment with nilotinib significantly reduces collagen and DDR1 gene expression (upregulated in AD brain), in association with inhibition of CSF DDR1. Pro-inflammatory cytokines, including interleukins and chemokines are reduced along with caspase-3 gene expression. Specific changes in vesicular transport, including the neurotransmitters dopamine and acetylcholine, and autophagy genes, including ATGs, indicate facilitation of autophagic flux and cellular trafficking. Specific genes that indicate vascular fibrosis, e.g. collagen and TGFs and vascular integrity (TIMPs) are altered by DDR1 inhibition with nilotinib. DDR1 knockout mice crossed with a model of vascular amyloidosis show similar reductions of collagen 4 levels and blood vessel thickness. Inhibition of DDR1 with nilotinib may be safe and effective adjunctive treatment strategy involving an oral drug that enters the CNS and adequately engages its target. DDR1 inhibition with nilotinib exhibits multi-modal effects not only on amyloid and tau clearance and dopamine neurotransmission but also on anti-inflammatory markers that may reduce cerebrovascular fibrosis.