Mechanisms of Protection in Early and Mid‐Stage Alzheimer’s Disease by Treatment with NAD+ Preserving Compound

Abstract Background Alzheimer’s disease (AD) currently affects around 6 million Americans and is growing exponentially with our aging population. Impaired homeostasis of nicotinamide adenine dinucleotide (NAD + ) impacts several neurodegenerative diseases, including AD. Aging and traumatic brain injury, two of the principle causes of AD, are also associated with impaired NAD + homeostasis. Method We measured NAD + levels in brain tissue from two different cohorts of patients with AD, along with matched controls, as well in 5xFAD mice and WT littermates. We also evaluated the efficacy of treating 5xFAD mice with the NAD + stabilizing compound P7C3‐A20, at various stages throughout disease progression. Outcome measures included neurobehavioral assay and immunohistochemical and biochemical assessment of pathology, as well as brain NAD + levels. Result We detected significantly decreased NAD + levels in the brains of human patients with AD, relative to matched control brain tissue. We also detected significantly decreased NAD + in the brains of 5xFAD mice, relative to WT littermates, throughout the disease process across young, mid, and old age. Treatment of 5xFAD mice with P7C3‐A20 restored NAD + levels in the brain of 5xFAD mice at the same time points, and also protected from cognitive decline and depression‐like behavior. Treatment with P7C3‐A20 also decreased Aβ plaque load, neuroinflammation, axonal degeneration, and blood‐brain barrier deterioration, in both male and female 5xFAD mice. Conclusion Disruption in NAD + homeostasis is a hallmark of AD, and we demonstrate here that treatment with the NAD + ‐stabilizing molecule P7C3‐A20 prevents and reverses AD‐like behavior and pathology in 5xFAD mice. This provides proof of principle for a potential new approach to treating patients with AD.