title: Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis.
abstract: Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral beta-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.
authors.affiliation: Neuropathology, Institute for Pathology, University of Basel, CH-4003 Basel, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Boncristiano
authors.forename: Michael E
authors.initials: ME
authors.lastname: Calhoun
authors.forename: Peter H
authors.initials: PH
authors.lastname: Kelly
authors.forename: Michelle
authors.initials: M
authors.lastname: Pfeifer
authors.forename: Luca
authors.initials: L
authors.lastname: Bondolfi
authors.forename: Martina
authors.initials: M
authors.lastname: Stalder
authors.forename: Amie L
authors.initials: AL
authors.lastname: Phinney
authors.forename: Dorothee
authors.initials: D
authors.lastname: Abramowski
authors.forename: Christine
authors.initials: C
authors.lastname: Sturchler-Pierrat
authors.forename: Albert
authors.initials: A
authors.lastname: Enz
authors.forename: Bernd
authors.initials: B
authors.lastname: Sommer
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology; D000682:Amyloid / Q000032:analysis; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000686:Amyloidosis / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D020532:Basal Nucleus of Meynert / Q000473:pathology; D002452:Cell Count; D048429:Cell Size; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000737:chemistry / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D016548:Prosencephalon / Q000201:enzymology / Q000473:pathology
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase