Beyond expectations: investigating nilotinib's potential in attenuating neurodegeneration in alzheimer's disease

Abstract

Neurodegenerative diseases, such as Alzheimer's disease (AD), pose a formidable global challenge. While therapeutic options are available, their limitations are significant, necessitating the development of innovative treatment approaches. Here, we highlight the importance of repurposing drugs and discuss the future of drug treatments for AD. We review the potential of tyrosine kinase inhibitors (TKI) for mitigating AD pathology and symptoms, as well as neurodegenerative processes more broadly. We focus on nilotinib, a selective BCR-ABL tyrosine kinase inhibitor, which has unique mechanisms of action involving the modulation of cell responses and removal of toxic proteins associated with AD pathogenesis. Encouraging studies have demonstrated its efficacy, calling for further investigation through clinical trials to assess its potential in various neurodegenerative conditions. However, despite these promising preclinical findings, no clinical studies have yet conclusively demonstrated its efficacy in treating AD. Considering the future directions in AD research, personalized medicine approaches hold promise by incorporating patient-specific factors, including sex and gender differences, to tailor nilotinib treatment for improved efficacy and safety profiles.

Keywords: Alzheimer disease; Autophagy; Memory; Neurodegeneration; Protein aggregates; Repurposed.

Fig. 1

Schematic depicting glial cell Aβ clearance. AD is characterized by Aβ accumulation, which can cause reactive gliosis in the brain. Nilotinib has been shown to have anti-inflammatory effects and to protect neurons from reactive microglia-induced inflammatory damage. (A) To protect neurons from injury by Aβ, microglia form a physical barrier around the Aβ plaque. (B) Microglial proteases cause Aβ degradation and increase Aβ clearance. (C) Microglial phagocytosis is enhanced by targeting the receptors and pathways involved in this response. (D) Anti-inflammatory cytokines promote microglial phagocytosis and Aβ clearance, whereas proinflammatory cytokines inhibit phagocytosis. (E) Astrocytes can be activated by cytokines secreted by microglia. (F) Aβ can cause microglia to become reactive and impair synaptic function. Reprinted from https://www.mdpi.com/2218-273X/13/2/313. Available under Creative Commons BY 4.0 license

Fig. 2

Reprinted from “Alzheimer’s Disease (AD) Treatment Model,” by BioRender.com (2024). Retrieved from https://app.biorender.com/biorender-templates/figures. Showing the most common drugs used in the treatment of AD; memantine functioning on the NMDA receptor and donepezil, galantamine, and rivastigmine working on acetylcholinesterase. Not pictured are the newest class of drugs, monoclonal antibodies, that target amyloid to decrease Aβ plaque burden

Fig. 3

Receptor Tyrosine Kinase (RTK) domains and activation process. RTKs are being investigated as therapeutic targets for neurodegenerative diseases such as AD. This graphic depicts RTK activation by their specific ligands followed by dimerization of RTKs. Intracellularly, autophosphorylation and phosphorylation of proteins attached to the intracellular domain of tyrosine activates downstream signaling. Reprinted from https://www.mdpi.com/2072-6694/12/8/2042#. Available under Creative Commons BY 4.0 license.

Fig. 4

Neuroprotective effects of nilotinib in Tg2576 mice by improving autophagic flux in VTA dopaminergic neurons, a pathway involved in cognition and motivation. (A) Tg2576 mice with impairment in autophagy, leading to decreased dopamine levels, cognitive deficits, and neurodegeneration. (B) Tg2576 mice treated with nilotinib, leading to enhanced autophagy function and restored dopamine levels, improved cognitive abilities, and neuroprotective effects. Adapted from “Targeting autophagy as a therapeutic strategy to prevent dopamine neuron loss in early stages of Alzheimer disease” by A. Nobili et al., 2021, Taylor & Francis, 17(5), 1278–1280. Adapted with permission from Taylor & Francis Ltd, available on https://www.tandfonline.com/doi/full/10.1080/15548627.2021.1909409.