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. 2023 May 16;20(1):116.
doi: 10.1186/s12974-023-02802-0.

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

Max Stevenson  1 , Rency Varghese  2 , Michaeline L Hebron  1 , Xiaoguang Liu  1 , Nick Ratliff  1 , Amelia Smith  1 , R Scott Turner  3 , Charbel Moussa  4
Affiliations

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

Max Stevenson et al. J Neuroinflammation. .

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 hippocampal volume loss. However, the mechanisms are unclear. Here, we explored unbiased next generation whole genome miRNA sequencing from AD patients CSF and 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. 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 genes that indicate vascular fibrosis, e.g., collagen, Transforming Growth Factors (TGFs) and Tissue Inhibitors of Metalloproteases (TIMPs) are altered by DDR1 inhibition with nilotinib. Specific changes in vesicular transport, including the neurotransmitters dopamine and acetylcholine, and autophagy genes, including ATGs, indicate facilitation of autophagic flux and cellular trafficking. Inhibition of DDR1 with nilotinib may be a safe and effective adjunct 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 but also on anti-inflammatory markers that may reduce cerebrovascular fibrosis.

Keywords: Alzheimer’s disease; Chemokines; Collagen; Cytokines; Discoidin domain receptor 1; MicroRNAs; Nilotinib.

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Conflict of interest statement

C.M. is an inventor on several US and international Georgetown University patents to use nilotinib and other tyrosine kinase inhibitors as a treatment for neurodegenerative diseases. Georgetown University and C.M are shareholders in KeifeRX LLC, a biopharmaceutical company, from which C.M. receives consulting fees and is a co-founder. C.M. receives consulting fees from SkyBio LLC and research grants from NIH–NIA and Sun Pharmaceuticals Advanced Research Corporation (SPARC). RST reports research support to Georgetown University from Alector, Biogen, Eisai, Janssen, Lilly, Roche/Genentech, Vaccinex, and Vivoryon. The remaining authors have no potential competing interests.

Figures

Fig. 1
Fig. 1
Unbiased next generation whole genome sequencing of CSF miRNA showed expression profiles of a total of 1050 miRNA between baseline and 12 months in the placebo (n = 11) and nilotinib groups (n = 12) (two-way ANOVA)
Fig. 2
Fig. 2
DDR1 is longitudinally inhibited in the CSF of AD patients treated with nilotinib. ELISA measurement of pan-tyrosine phosphorylated DDR1 (pDDR1) shows the slope (m) of log10 linear regression of mean difference values in the CSF of A) AD patients from baseline-end of treatment, indicating (rising slopes) an increase in active pDDR1 level over time. Nilotinib treatment B) results in slower slope (m) of log10 linear regression of mean difference values between baseline and end of treatment in AD patients treated with nilotinib, indicating reduction of pDDR1 (active). N = 12 placebo and n = 12 in nilotinib. C) measurement of plasma Aβ42 and pTau217 using Biofluid Biomarker Assay via SQUID IMR (Immuno Magnetic Reagents) Platform (MagQu Co., Ltd). N = 12 placebo and N = 10 nilotinib. Graphed as mean ± standard error of the mean. The changes in the ratio of Aβ42/pTau (217) across each group were compared using a one‐tailed unpaired t‐test with Welch's corrections. Asterisks denote actual P‐value significances (*P < 0.05) between groups and are noted in the figure. Statistical analysis was performed using GraphPad Prism, version 9.1.2 (GraphPad Software Inc.)
Fig. 3
Fig. 3
miRNAs that target inflammation are significantly reduced in nilotinib treated patients. A total of 17 microRNAs (1.6%) were significantly different between the placebo and nilotinib groups, accounting for both treatment and time. Ingenuity Pathway Analysis of microRNA matched associated mRNAs or targets that are experimentally validated from TarBase, miRecords, as well as highly predicted miRNA–mRNA interactions from TargetScan and revealed that 9 of these microRNAs are associated with genes that regulate inflammation. N = 11 placebo, n = 12 nilotinib
Fig. 4
Fig. 4
miRNAs that target vascular fibrosis are significantly reduced in nilotinib treated patients. A total of 17 microRNAs (1.6%) were significantly different between the placebo and nilotinib groups, accounting for both treatment and time. Ingenuity Pathway Analysis of microRNA matched associated mRNAs or targets that are experimentally validated from TarBase, miRecords, as well as highly predicted miRNA–mRNA interactions from TargetScan and revealed that 7 of these microRNAs are associated with genes that regulate collagen expression. N = 11 placebo, n = 12 nilotinib
Fig. 5
Fig. 5
miRNAs that target autophagy and dopamine metabolism are significantly altered between placebo and nilotinib. A total of 17 microRNAs (1.6%) were significantly different between the placebo and nilotinib groups, accounting for both treatment and time. Ingenuity Pathway Analysis of microRNA matched associated mRNAs or targets that are experimentally validated from TarBase, miRecords, as well as highly predicted miRNA–mRNA interactions from TargetScan and revealed that 14 of these microRNAs are associated with genes that control autophagy and dopamine metabolism. N = 11 placebo, n = 12 nilotinib
Fig. 6
Fig. 6
Tyrosine kinase DDR1 inhibition with nilotinib. Treatment of AD patients with nilotinib may induce multiple mechanisms that include activation of genes that control the execution and completion of autophagy, suggesting clearance of intracellular amyloid and tau that would perhaps reduce plaque burden and affect plasma amyloid and tau. Nilotinib treatment led to downregulation of several pro-inflammatory makers along with reduction of collagen, TIMPs and TGFs that maintain blood vessel integrity and prevent vascular fibrosis. Nilotinib treatment leads to reduction of dopamine breakdown probably via altered vesicular transport and reduction of COMT
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