Regional cholinergic denervation of cortical microvessels and nitric oxide synthase-containing neurons in Alzheimer's disease

• Published in: Neuroscience Vol. 92; no. 1; pp. 163 - 175
• Main Authors: Tong, X.K., Hamel, E.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.01.1999; Elsevier
• Subjects: acetylcholine; Adult; Afferent Pathways - physiology; Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; basal forebrain; Biological and medical sciences; Blood Vessels - innervation; cerebral blood flow; cerebral blood vessels; Cerebral Cortex - blood supply; Choline O-Acetyltransferase - metabolism; Cholinergic Fibers - enzymology; Cholinergic Fibers - physiology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; dementia; Denervation; Female; Humans; Male; Medical sciences; Microcirculation - physiology; NADPH Dehydrogenase - metabolism; Neurology; Neurons - enzymology; nitric oxide; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type I; Perfusion; Reference Values; cerebral blood vessels; nitric oxide; PBS, phosphate-buffered saline; AD, Alzheimer's disease; NO, nitric oxide; basal forebrain; cerebral blood flow; dementia; ChAT, choline acetyltransferase; acetylcholine; NOS, nitric oxide synthase; NADPH-D, reduced nicotinamide adenine dinucleotide phosphate-diaphorase; Human; Regional blood flow; Cholinergic neuron; Nervous system diseases; Enzyme; Alzheimer disease; Pathogenesis; Central nervous system; Nitric-oxide synthase; Cerebral disorder; Nitric oxide; Central nervous system disease; Degenerative disease; Hemodynamics; Oxidoreductases; Brain (vertebrata); Denervation
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(98)00750-7

In the present study, we investigated in the human cerebral cortex whether, as in the rat, basal forebrain cholinergic neurons innervate cortical microvessels and nitric oxide synthase-containing neurons and, further, we compared the status of this innervation between aged controls and neuropathologically confirmed cases of Alzheimer's disease. Using immunocytochemistry of choline acetyltransferase coupled to reduced nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry, we show in young human subjects the presence of a cholinergic input to the cortical microcirculation, and of numerous perisomatic and peridendritic contacts between cholinergic nerve terminals and reduced nicotinamide adenine dinucleotide phosphate-diaphorase neurons. A regional cholinergic denervation of both cortical microvessels and reduced nicotinamide adenine dinucleotide phosphate-diaphorase neurons was found in Alzheimer's disease patients as compared to aged controls, and it paralleled the loss of total cholinergic nerve terminals in the corresponding areas of the cerebral cortex. The vascular denervation was more severe in the temporal (77%, P<0.05) than in the frontal (48%, not significant) cortex, and the reduced nicotinamide adenine dinucleotide phosphate-diaphorase intracortical neurons were similarly deprived of their cholinergic input ( P<0.01) in both regions. Interestingly, a significant increase in luminal diameter (48%, P<0.01) and area (>160%, P<0.01) of perfused microvessels was found in Alzheimer's tissues, possibly a consequence of both loss of neurogenic input and structural changes in blood vessel walls. The data indicate that intracortical microvessels and nitric oxide neurons in Alzheimer's disease are deprived of a cholinergic neurogenic control, a situation which is likely to result in a compromised ability to adapt cortical perfusion to neuronal activation during functional tasks related to cognition, arousal and attention. We conclude that such deficits in neurovascular regulation are likely to be an important pathogenic factor underlying cerebral blood flow dysfunctions in Alzheimer's disease.