RESUMEN
We examined presynaptic cholinergic markers and beta-secretase activity during progressive central nervous system amyloidogenesis in Tg2576 Alzheimer mice (transgenic for human amyloid precursor protein Swedish mutation; hAPPswe). At 14, 18, and 23 months of age there were no significant differences between wild-type and transgenic mice in four distinct central nervous system cholinergic indices--choline acetyltransferase and acetylcholinesterase activities, and binding to vesicular acetylcholine transporter and Na(+)-dependent high-affinity choline uptake sites. A novel enzyme-linked immunosorbent assay measuring only the secreted human beta-secretase cleavage product (APPsbetaswe) of APPswe also revealed no change with aging in Tg2576 mouse brain. In contrast, transgenic but not wild-type mice exhibited an age-dependent increase in soluble Abeta40 and Abeta42 levels and progressive amyloid deposition in brain. Thus, aging Tg2576 mice exhibited presynaptic cholinergic integrity despite progressively increased soluble Abeta40 and Abeta42 levels and amyloid plaque density in brain. Older Tg2576 mice may best resemble preclinical or early stages of human Alzheimer's disease with preserved presynaptic cholinergic innervation. Homeostatic APPsbetaswe levels with aging suggest that progressive amyloid deposition in brain results not from increased beta-secretase cleavage of APP but from impaired Abeta/amyloid clearance mechanisms.
Asunto(s)
Acetilcolinesterasa/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/metabolismo , Colina O-Acetiltransferasa/metabolismo , Envejecimiento/fisiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide , Precursor de Proteína beta-Amiloide/genética , Animales , Biomarcadores , Encéfalo/enzimología , Modelos Animales de Enfermedad , Endopeptidasas , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Fármacos Neuromusculares Despolarizantes/metabolismo , Piperidinas/metabolismoRESUMEN
Corticotroph (basophil) invasion or the migration of corticotroph cells into the pars nervosa of the human pituitary gland was found in 35 of 767 (4.4%) consecutive pituitaries obtained at autopsy. The degree of invasion increased with patient age and extensive invasion was more common in men than in women. Immunoreactive ACTH, ß-MSH, α-MSH, and galanin were detected both in the anterior lobe and invading corticotroph cells in approximately equal frequency. Fewer cells stained positively for α-MSH than for the three other peptides in both the anterior lobe and invading corticotrophs. Twelve corticotropic pituitary adenomas obtained surgically from patients with Cushing's disease were also examined and expressed varying degrees of immunoreactivity for ACTH, α MSH, ß-MSH and galanin. Staining for all major pituitary hormones revealed only ACTH in the invading basophil cells. Peptidylglycine α-amidating monooxygenase (PAM) was present in the anterior pituitary, in invading corticotroph cells, and in some cells lining the cysts of the pars intermedia zone. PAM immunoreactivity was also detected in 4/12 corticotroph adenomas. These results indicate that corticotroph cells invading the pars nervosa are immunohistochemically similar to anterior lobe corticotrophs and have the ability to amidate various peptides such as proopiomelanocortin cleavage products and galanin with PAM.