Nitric oxide signaling in Alzheimer's disease: A double-edged sword.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral changes, primarily affecting the elderly population. Despite extensive research, the exact pathogenesis of AD remains elusive, with proposed mechanisms involving amyloid-β accumulation, tau protein hyperphosphorylation, oxidative stress, neuroinflammation, and neuronal apoptosis. Nitric oxide (NO), a gaseous signaling molecule synthesized by nitric oxide synthases (NOS), plays dual roles in AD pathophysiology-acting as both a neuroprotective and neurotoxic agent depending on its concentration and cellular context. The NO-cGMP signaling pathway is integral to synaptic plasticity, long-term potentiation, and neurogenesis, processes essential for memory and learning. Conversely, excessive NO generation via inducible NOS contributes to neuroinflammation, oxidative and nitrosative stress, and neuronal damage. NO also modulates cerebral blood flow, neuroplasticity, and myelination, influencing AD progression. Current pharmacological management focuses on symptomatic relief through cholinesterase inhibitors and NMDA receptor antagonists, while emerging NO-based therapies and PDE-5 inhibitors show potential neuroprotective benefits. Additionally, anti-inflammatory agents and herbal compounds targeting NO-mediated pathways, exhibit promising neuroprotective properties. A deeper understanding of NO's dualistic role may provide novel therapeutic strategies for mitigating AD progression and enhancing cognitive resilience.