Evaluation of nNOS-mediated AβO Neuropathology as Potential Therapeutic Applications in Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by pathogenic accumulation of amyloid beta (Aβ) oligomers in a mortality-inducing cognitive decline self-reinforcing feedback loop. A key driver of AD pathology is Aβ oligomer (AβO) neurotoxicity, precipitating dysfunction in synaptic transmission and ultimately resulting in neuronal death. Recent studies show that in both death signaling pathways activated by AβO involve neuronal nitric oxide synthase (nNOS) and thus presence of nNOS may complicate AD progression in two avenues: 1. Complication via association with hyperphosphorylated tau, and 2. Complication via pro-neuroinflammatory signaling. The purpose of this study is to assess whether nNOS inhibition could be a therapeutic target for AD if nNOS activity increases AβO-induced pathological signaling. Assessment of nNOS will be conducted in both Alzheimer's disease models, MC65 and HT22, via tau phosphorylation and neuronal death. Treating cells with nNOS inhibitors will determine the potential of nNOS inhibition to alleviate AβO-induced neurotoxic results. AβO exposure elevates nNOS, tau phosphorylation, and neuronal death; however, preliminary results indicate treatment with the selective nNOS inhibitor significantly reduced all three. This study seeks to determine the role of nNOS in Aβ-driven AD pathologyand support nNOS inhibition as a viable therapeutic strategy for Alzheimer's disease.