  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 vessels diameter control could be responsible for the impaired
neurovascular coupling observed in AD, blood vessels reactivity in response to
different pharmacological stimulations was examined in double transgenic
APPxPS1 mice model of AD. Blood vessels movements were monitored using infrared
videomicroscopy ex vivo, in cortical slices of 8 month-old APPxPS1 and wild
type (WT) mice. We quantified vasomotor responses induced either by direct
blood vessel stimulation with a thromboxane A 2 analogue, the U46619
(9,11-dideoxy-11a,9a-epoxymethanoprostaglandin F2) or via the stimulation of
interneurons with 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 vessel
diameter 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 interneurons with 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 vessels following 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.
