The Role of c-Abl in Alzheimer's Disease: Guilty or not Guilty?

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Extracellular senile plaques composed of amyloid-β (Aβ) peptides, intracellular neurofibrillary tangles (NFTs) containing the hyperphosphorylated tau protein, excessive production of reactive oxygen species (ROS) and neuroinflammation are crucial contributing factors to the pathological mechanisms of AD. The nonreceptor tyrosine kinase c-Abl plays a complex dual role in AD through the regulation of signaling pathways such as oxidative stress, DNA repair, and apoptosis. c-Abl mitigates early neuronal damage by activating antioxidant enzymes and potentially promoting homologous recombination (HR) repair. However, its aberrant activation is associated with Aβ plaque formation, tau phosphorylation, neuronal cell death, and synaptic dysfunction. Its synergistic interaction with Aβ and tau exacerbates the neurodegenerative pathology. This article provides a systematic review of the molecular mechanisms of c-Abl in AD, including its dual role in oxidative stress, synergistic regulation of neuronal function with Aβ and the tau protein, involvement in the maintenance of genomic stability, and potential as a therapeutic target.