15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Alzheimer-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 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 A2 analogue, the U46619 (9,11-dideoxy-11a,9a-epoxymethanoprostaglandin F2α) 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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Area Under Curve; Blood Vessels; Brain; Cerebrovascular Circulation; Dimethylphenylpiperazinium Iodide; Disease Models, Animal; Ganglionic Stimulants; Humans; In Vitro Techniques; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuropeptide Y; Presenilin-1; Vasoconstrictor Agents; Vasodilation

Amyloid-beta (A beta)-peptides are involved in the pathophysiology of Alzheimer's dementia. We studied the effects of A beta on selected constrictor responses of cerebral circulation. Mice were anesthetized (by using urethane-chloralose) and equipped with a cranial window. Arterial pressure and blood gases were monitored and controlled. Cerebral blood flow (CBF) was monitored by a laser Doppler probe. Topical superfusion with A beta 1-40 (0.1-10 microM), but not with the reverse peptide A beta 40-1, reduced resting CBF (-29 +/- 4% at 5 microM; P < 0.05) and augmented the reduction in CBF produced by the thromboxane analog U-46619 (+45 +/- 3% at 5 microM; P < 0.05). A beta 1-40 or A beta 1-42 did not affect the reduction in CBF produced by hypocapnia. The reduction in resting CBF and the enhancement of vasoconstriction were reversed by treatment with the free radical scavengers superoxide dismutase or manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin. Substitution of the methionine residue in position 35 with norleucine, a mutation that abolishes the ability of A beta to produce free radicals, abolished its vascular effects. Nanomolar concentrations of A beta 1-40 constricted isolated pressurized middle cerebral artery segments with intrinsic tone (-16 +/- 3% at 100 nM; P < 0.05). We conclude that A beta acts directly on cerebral arteries to produce vasoconstriction and to enhance selected constrictor responses. The evidence supports the idea that A beta-induced production of reactive oxygen species plays a role in this effect. The vascular actions of A beta may contribute to the deleterious effects resulting from accumulation of this peptide in Alzheimer's dementia.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebrovascular Circulation; Free Radical Scavengers; Hypocapnia; Laser-Doppler Flowmetry; Male; Metalloporphyrins; Mice; Mice, Inbred C57BL; Peptide Fragments; Reactive Oxygen Species; Superoxide Dismutase; Vasoconstriction; Vasoconstrictor Agents