Publication date: Jun 06, 2019
Nilotinib, a tyrosine kinase inhibitor developed by Novartis (NYSE:NVS) and approved for leukemia treatment as Tasigna, is being tested in a phase-2 trial for treating AD.
Nilotinib can inhibit multiple tyrosine kinase receptors, including c-ABL, EphA4, DDR1, PDGFRα/β.
First, Nilotinib inhibits the tyrosine kinase c-ABL, which is activated in AD dystrophic neurites.
Supporting this is the finding of significantly decreased gliosis and reduced escape latency in the Morris water maze in an AD mouse model treated with imatinib, a broad tyrosine kinase inhibitor of cABL (similar to Nilotinib), compared to untreated controls.
Corroborating the potential antioxidant effect, ST1571, a broad tyrosine kinase inhibitor that also inhibits c-ABL, inhibited H O -mediated apoptosis in cultured hippocampal neurons and Nilotinib treatment reduced oxidative stress in a rat model of liver toxicity.
The macroautophagy defect in AD and PD, however, occurs mostly in distal axons, where a profound accumulation of autophagosomes and autophagic vacuoles accumulate in axonal swellings, which is thought to be caused by defective lysosomal digestion or defective autophagosomes transport from the distal axon to the proximal axon and cell body where lysosomal acidification and bulk digestion occurs.
Moreover, in AD brain, many autophagy transcripts are upregulated and the neuron body has the appearance of overactive autophagy with depleted organelles, such as mitochondria, which could be reflective of autophagic programmed cell death.
Chaperone-mediated autophagy degrades strictly old proteins, such as α-synuclein, tau, and amyloid, and is dependent on two proteins, which are reduced in brain regions from PD patients, but not from AD.
EphA4 is activated by β-amyloid oligomers, the toxic fragments that accumulate in AD, and the association of SORLA with EphA4 significantly reduces β-amyloid-mediated EphA4 activation in cultured cortical neurons and in mouse hippocampus injected with β-amyloid.
DDR1 is expressed in oligodendrocytes and endothelial cells, and its expression is increased in AD brain.
Collagen activated DDR1 can up-regulate metalloproteinase 9 (MMP-9), which can degrade basement membrane, leading to compromised integrity of the brain blood barrier (BBB), an early biomarker of AD.
However, blocking DDR1 signaling in oligodendrocytes could prevent MMP-9 mediated myelin protein degradation that leads to white matter lesions in AD.
MMP-9 is increased in AD extracellular matrix, presumably through DDR1 activation, and increased MMP-9 can degrade nerve growth factor leading to the loss of trophic support needed for cell survival and maintenance.
In sum, Nilotinib-mediated DDR1 inhibition could decrease MMP-9 levels, thereby reducing MMP-9-mediated degradation myelin proteins, NGF, collagen VI, and additionally, reduce collagen-mediated microglia activation.