Repurposing Nilotinib in a Metabolically Compromised Mouse Model of Alzheimer's Disease

Repurposing Nilotinib in a Metabolically Compromised Mouse Model of Alzheimer's Disease

Alvin Sherman Library

Diet-related metabolic disorders, including obesity, prediabetes, and type 2 diabetes, significantly increase the risk of Alzheimer's disease (AD). Despite substantial research, effective disease-modifying therapies remain limited. Nilotinib, a tyrosine kinase inhibitor approved for leukemia, has shown neuroprotective effects in preclinical AD models, including reduced amyloid-β pathology and improved cognition. In vitro studies also suggest nilotinib enhances mitochondrial bioenergetics. However, its efficacy under conditions of metabolic dysfunction remains unclear. This study therefore evaluated the effects of nilotinib in an AD mouse model with diet-induced metabolic impairment. Male and female B6129SF1/J control and 3xTg-AD mice were fed a low-fat (LFD) or high-fat (HFD) diet starting at ~12 weeks. After 3 months of dietary intervention, mice received daily intraperitoneal injections of nilotinib (6 mg/kg) or vehicle. Metabolic outcomes were assessed using glucose tolerance testing, and behavioral assays were conducted 8 weeks after treatment initiation to assess locomotor activity, anxiety-like behavior, and cognition function. HFD induced metabolic impairments in 3xTg-AD mice, including increased weight, adiposity, and impaired glucose tolerance, with more pronounced effects in females. Regardless of diet, 3xTg-AD mice showed reduced locomotor activity and exploratory behavior relative to controls. Nilotinib partially improved these deficits and reduce anxiety-like behavior in male 3xTg-AD mice on LFD, with trends toward improved spatial recognition and long-term spatial memory. These findings suggest nilotinib may confer cognitive benefits in AD, with treatment responsiveness influenced by sex and metabolic state. Ongoing analyses of mitochondrial bioenergetics and neuropathology will further clarify the underlying mechanisms and therapeutic potential of nilotinib in AD.