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Distinct glutaminyl cyclase expression in Edinger-Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Abeta pathology in Alzheimer's disease.
Acta Neuropathol ; 120(2): 195-207, 2010 Aug.
Article en En | MEDLINE | ID: mdl-20383514
ABSTRACT
Glutaminyl cyclase (QC) was discovered recently as the enzyme catalyzing the pyroglutamate (pGlu or pE) modification of N-terminally truncated Alzheimer's disease (AD) Abeta peptides in vivo. This modification confers resistance to proteolysis, rapid aggregation and neurotoxicity and can be prevented by QC inhibitors in vitro and in vivo, as shown in transgenic animal models. However, in mouse brain QC is only expressed by a relatively low proportion of neurons in most neocortical and hippocampal subregions. Here, we demonstrate that QC is highly abundant in subcortical brain nuclei severely affected in AD. In particular, QC is expressed by virtually all urocortin-1-positive, but not by cholinergic neurons of the Edinger-Westphal nucleus, by noradrenergic locus coeruleus and by cholinergic nucleus basalis magnocellularis neurons in mouse brain. In human brain, QC is expressed by both, urocortin-1 and cholinergic Edinger-Westphal neurons and by locus coeruleus and nucleus basalis Meynert neurons. In brains from AD patients, these neuronal populations displayed intraneuronal pE-Abeta immunoreactivity and morphological signs of degeneration as well as extracellular pE-Abeta deposits. Adjacent AD brain structures lacking QC expression and brains from control subjects were devoid of such aggregates. This is the first demonstration of QC expression and pE-Abeta formation in subcortical brain regions affected in AD. Our results may explain the high vulnerability of defined subcortical neuronal populations and their central target areas in AD as a consequence of QC expression and pE-Abeta formation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácido Pirrolidona Carboxílico / Locus Coeruleus / Sustancia Gris Periacueductal / Aminoaciltransferasas / Núcleo Basal de Meynert / Enfermedad de Alzheimer Límite: Adult / Aged / Aged80 / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Acta Neuropathol Año: 2010 Tipo del documento: Article País de afiliación: Alemania

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácido Pirrolidona Carboxílico / Locus Coeruleus / Sustancia Gris Periacueductal / Aminoaciltransferasas / Núcleo Basal de Meynert / Enfermedad de Alzheimer Límite: Adult / Aged / Aged80 / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Acta Neuropathol Año: 2010 Tipo del documento: Article País de afiliación: Alemania
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