Neuritin improves cognitive impairments in APP/PS1 Alzheimer's disease mice model by mitigating neuronal ferroptosis via PI3K/Akt activation.

The neurotrophic factor Neuritin is known to enhance cognitive capacity and to mitigate synaptic impairments in the APP/PS1 Alzheimer's disease (AD) mouse model, suggesting therapeutic potential for clinical treatment. However, the core molecular mechanisms remain elusive. Ferroptosis, a form of programmed cell death linked to iron dysregulation and oxidative stress, contributes to neurodegeneration in AD in part by accelerating amyloid-β deposition and neurofibrillary tangle formation. Here we examined if Neuritin can mitigate cognitive decline and neural degeneration in AD model mice by suppressing ferroptosis. Age-dependent cognitive decline was associated with Neuritin downregulation and increased ferroptosis in the hippocampus. Intracerebroventricular injection of exogenous Neuritin mitigated spatial and fear learning deficits as well as neural oxidative stress, apoptosis, and ferroptosis in the hippocampus without causing deleterious side effects. Neuritin injection also upregulated the activity of NAD+ kinase (NADK), the enzyme responsible for converting NAD to anti-ferroptotic NADPH, in the hippocampus of AD mice as well as in cultured hippocampal neurons. Reduced Neuritin expression in the hippocampus AD mice was associated with reduced phosphorylation (activation) of Akt (p-Akt), and Neuritin administration enhanced p-Akt expression in both HT22 cells and AD model mice. Conversely, blocking the PI3K/Akt pathway in HT22 cells reversed the Neuritin-induced increase in NADK activity and reduction in ferroptosis, indicating that Neuritin protects neurons from AD-induced damage by enhancing NADK activity through the PI3K/Akt pathway. Collectively, our results support Neuritin upregulation as a potential therapeutic strategy for early-phase AD.