Impaired neurovascular coupling in the APPxPS1 mouse model of Alzheimerâs disease

The tight coupling between neuronal activity and the local increase of blood flow termed neurovascular coupling is essential for normal brain function. This mechanism of regulation is compromised in Alzheimer's Disease (AD). In order to determine whether a purely vascular dysfunction or a neuronal alteration of blood vesselsdiameter control could be responsible for the impaired neurovascular coupling observed in AD, blood vesselsreactivity in response to different pharmacological stimulations was examined in double transgenic APPxPS1 mice model of AD. Blood vesselsmovements were monitored using infrared videomicroscopy ex vivo, in cortical slices of 8 month-old APPxPS1 and wild type (WT) mice. We quantified vasomotorresponses induced either by direct blood vesselstimulation with a thromboxane A 2 analogue, the U46619 (9,11-dideoxy-11a,9a-epoxymethanoprostaglandin F2) or via the stimulation of interneuronswith the nicotinic acetylcholine receptor(nAChRs) agonist DMPP (1,1-Dimethyl-4-phenylpiperazinium iodide). Using both types of stimulation, no significant differences were detected for the amplitude of blood vesseldiameter changes between the transgenic APPxPS1 mice model of AD and WT mice, although the kinetics of recovery were slower in APPxPS1 mice. We find that activation of neocortical interneuronswith DMPP induced both vasodilation via Nitric Oxide (NO) release and constriction via Neuropeptide Y (NPY) release. However, we observed a smaller proportion of reactive blood vesselsfollowing a neuronal activation in transgenic mice compared with WT mice. Altogether, these results suggest that in this mouse model of AD, deficiency in the cortical neurovascular coupling essentially results from a neuronal rather than a vascular dysfunction.