LAUSR

Abstract Nitric oxide (•NO)‐dependent pathways and cerebrovascular dysfunction have been shown to contribute to the cognitive decline and neurodegeneration observed in Alzheimer's disease (AD) but whether they represent initial factors or later changes of the disease is still a matter of debate. In this work, we aimed at investigating whether and to what extent neuronal‐derived •NO signaling and related neurovascular coupling are impaired along aging in the hippocampus of the triple transgenic mouse model of Alzheimer's Disease (3xTg‐AD). We performed a longitudinal study combining behavior studies, in vivo simultaneous measurements of •NO concentration gradients and cerebral blood flow (CBF), along with detection of NO synthase (NOS) and markers of nitroxidative stress. Our results revealed an impairment in the neurovascular coupling along aging in the 3xTg‐AD mice which preceded obvious cognitive decline. This impairment was characterized by diminished CBF changes in response to normal or even increased •NO signals and associated with markers of nitroxidative stress. The results suggest that impairment in neurovascular coupling is primarily due to cerebrovascular dysfunction, rather than due to dysfunctional •NO signaling from neurons to blood vessels. Overall, this work supports cerebrovascular dysfunction as a fundamental underlying process in AD pathology. Graphical abstract Figure. No caption available. HighlightsNeurovascular coupling and nitrergic signaling pathways are altered in Alzheimer's.The dysfunction in neurovascular coupling does not relate to nitric oxide signaling.Neurovascular coupling impairment appears to be primarily of cerebrovascular origin.