β-amyloid excitotoxicity in rat magnocellular nucleus basalis. Effect of cortical deafferentation on cerebral blood flow regulation and implications for Alzheimer's disease

Tibor Harkany, B. Penke, Paul G M Luiten

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Abstract

Alzheimer's disease is the most common type of dementia with a still largely unclear etiopathology. One of the factors that may directly contribute to the development and progression of the disorder is the abundant accumulation of β-amyloid peptides (Aβ) in senile plaques. In the present account we review coherent in vivo experimental evidence that Aβ infusion into the rat magnocellular nucleus basalis (MBN) induces abrupt and persistent behavioral dysfunctions, perturbations of sensory information processing, storage, and retrieval. These substantial behavioral changes are due to the loss of cholinergic neurons in the MBN and their ascending projections to the frontoparietal cortex. Both neuroanatomical and neurochemical observations pinpoint that infusion of Aβ into the rat basal forebrain significantly decreases choline-acetyltransferase and acetylcholinesterase activities and the population of - probably - M2 muscarinic acetylcholine receptors in the cerebral cortex. Neuropharmacological data indicate that Aβ toxicity is mediated by an excitotoxic cascade involving blockade of astroglial glutamate uptake, sustained activation of N-methyl-D-aspartate receptors and an overt intracellular Ca2+ influx. These changes are associated with increased nitric oxide synthase activity in cortical target areas that may directly lead to the generation of free radicals. Besides, as microvessels of the neocortex receive direct input from the MBN we assume that the loss of cholinergic innervation and hence that of tonic cholinergic vasoregulation ultimately leads to disturbances of vascular (endothelial) function and nutrient supply that may directly enhance neuronal vulnerability during aging and in Alzheimer's disease.

Original languageEnglish
Pages (from-to)374-386
Number of pages13
JournalAnnals of the New York Academy of Sciences
Volume903
Publication statusPublished - 2000

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Cerebrovascular Circulation
Amyloid
Cholinergic Agents
Rats
Alzheimer Disease
Blood
Cholinergic Neurons
Choline O-Acetyltransferase
Information Storage and Retrieval
Neocortex
Amyloid Plaques
Muscarinic Receptors
Acetylcholinesterase
Microvessels
N-Methyl-D-Aspartate Receptors
Automatic Data Processing
Nitric Oxide Synthase
Cerebral Cortex
Free Radicals
Blood Vessels

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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title = "β-amyloid excitotoxicity in rat magnocellular nucleus basalis. Effect of cortical deafferentation on cerebral blood flow regulation and implications for Alzheimer's disease",
abstract = "Alzheimer's disease is the most common type of dementia with a still largely unclear etiopathology. One of the factors that may directly contribute to the development and progression of the disorder is the abundant accumulation of β-amyloid peptides (Aβ) in senile plaques. In the present account we review coherent in vivo experimental evidence that Aβ infusion into the rat magnocellular nucleus basalis (MBN) induces abrupt and persistent behavioral dysfunctions, perturbations of sensory information processing, storage, and retrieval. These substantial behavioral changes are due to the loss of cholinergic neurons in the MBN and their ascending projections to the frontoparietal cortex. Both neuroanatomical and neurochemical observations pinpoint that infusion of Aβ into the rat basal forebrain significantly decreases choline-acetyltransferase and acetylcholinesterase activities and the population of - probably - M2 muscarinic acetylcholine receptors in the cerebral cortex. Neuropharmacological data indicate that Aβ toxicity is mediated by an excitotoxic cascade involving blockade of astroglial glutamate uptake, sustained activation of N-methyl-D-aspartate receptors and an overt intracellular Ca2+ influx. These changes are associated with increased nitric oxide synthase activity in cortical target areas that may directly lead to the generation of free radicals. Besides, as microvessels of the neocortex receive direct input from the MBN we assume that the loss of cholinergic innervation and hence that of tonic cholinergic vasoregulation ultimately leads to disturbances of vascular (endothelial) function and nutrient supply that may directly enhance neuronal vulnerability during aging and in Alzheimer's disease.",
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T1 - β-amyloid excitotoxicity in rat magnocellular nucleus basalis. Effect of cortical deafferentation on cerebral blood flow regulation and implications for Alzheimer's disease

AU - Harkany, Tibor

AU - Penke, B.

AU - Luiten, Paul G M

PY - 2000

Y1 - 2000

N2 - Alzheimer's disease is the most common type of dementia with a still largely unclear etiopathology. One of the factors that may directly contribute to the development and progression of the disorder is the abundant accumulation of β-amyloid peptides (Aβ) in senile plaques. In the present account we review coherent in vivo experimental evidence that Aβ infusion into the rat magnocellular nucleus basalis (MBN) induces abrupt and persistent behavioral dysfunctions, perturbations of sensory information processing, storage, and retrieval. These substantial behavioral changes are due to the loss of cholinergic neurons in the MBN and their ascending projections to the frontoparietal cortex. Both neuroanatomical and neurochemical observations pinpoint that infusion of Aβ into the rat basal forebrain significantly decreases choline-acetyltransferase and acetylcholinesterase activities and the population of - probably - M2 muscarinic acetylcholine receptors in the cerebral cortex. Neuropharmacological data indicate that Aβ toxicity is mediated by an excitotoxic cascade involving blockade of astroglial glutamate uptake, sustained activation of N-methyl-D-aspartate receptors and an overt intracellular Ca2+ influx. These changes are associated with increased nitric oxide synthase activity in cortical target areas that may directly lead to the generation of free radicals. Besides, as microvessels of the neocortex receive direct input from the MBN we assume that the loss of cholinergic innervation and hence that of tonic cholinergic vasoregulation ultimately leads to disturbances of vascular (endothelial) function and nutrient supply that may directly enhance neuronal vulnerability during aging and in Alzheimer's disease.

AB - Alzheimer's disease is the most common type of dementia with a still largely unclear etiopathology. One of the factors that may directly contribute to the development and progression of the disorder is the abundant accumulation of β-amyloid peptides (Aβ) in senile plaques. In the present account we review coherent in vivo experimental evidence that Aβ infusion into the rat magnocellular nucleus basalis (MBN) induces abrupt and persistent behavioral dysfunctions, perturbations of sensory information processing, storage, and retrieval. These substantial behavioral changes are due to the loss of cholinergic neurons in the MBN and their ascending projections to the frontoparietal cortex. Both neuroanatomical and neurochemical observations pinpoint that infusion of Aβ into the rat basal forebrain significantly decreases choline-acetyltransferase and acetylcholinesterase activities and the population of - probably - M2 muscarinic acetylcholine receptors in the cerebral cortex. Neuropharmacological data indicate that Aβ toxicity is mediated by an excitotoxic cascade involving blockade of astroglial glutamate uptake, sustained activation of N-methyl-D-aspartate receptors and an overt intracellular Ca2+ influx. These changes are associated with increased nitric oxide synthase activity in cortical target areas that may directly lead to the generation of free radicals. Besides, as microvessels of the neocortex receive direct input from the MBN we assume that the loss of cholinergic innervation and hence that of tonic cholinergic vasoregulation ultimately leads to disturbances of vascular (endothelial) function and nutrient supply that may directly enhance neuronal vulnerability during aging and in Alzheimer's disease.

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