title: Selective cholinergic denervation, independent from oxidative stress, in a mouse model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by increases in amyloid-beta (Abeta) peptides, neurofibrillary tangles, oxidative stress and cholinergic deficits. However, the selectivity of these deficits and their relation with the Abeta pathology or oxidative stress remain unclear. We therefore investigated amyloidosis-related changes in acetylcholine (ACh) and serotonin (5-HT) innervations of hippocampus and parietal cortex by quantitative choline acetyltransferase (ChAT) and 5-HT immunocytochemistry, in 6, 12/14 and 18 month-old transgenic mice carrying familial AD-linked mutations (hAPP(Sw,Ind)). Further, using manganese superoxide dismutase (MnSOD) and nitrotyrosine immunoreactivity as markers, we evaluated the relationship between oxidative stress and the ACh deficit in 18 month-old mice. Thioflavin-positive Abeta plaques were seen in both regions at all ages; they were more numerous in hippocampus and increased in number (>15-fold) and size as a function of age. A majority of plaques exhibited or were surrounded by increased MnSOD immunoreactivity, and dystrophic ACh or 5-HT axons were seen in their immediate vicinity. Counts of immunoreactive axon varicosities revealed significant decreases in ACh innervation, with a sparing of the 5-HT, even in aged mice. First apparent in hippocampus, the loss of ACh terminals was in the order of 20% at 12/14 months, and not significantly greater (26%) at 18 months. In parietal cortex, the ACh denervation was significant at 18 months only, averaging 24% across the different layers. Despite increased perivascular MnSOD immunoreactivity, there was no evidence of dystrophic ACh varicosities or their accentuated loss in the perivascular area. Moreover, there was virtually no sign of tyrosine nitration in ChAT nerve terminals or neuronal cell bodies. These data suggest that aggregated Abeta exerts an early, non-selective and focal neurotoxic effect on both ACh and 5-HT axons, but that a selective, plaque- and oxidative stress-independent diffuse cholinotoxicity, most likely caused by soluble Abeta assemblies, is responsible for the hippocampal and cortical ACh denervation.
authors.affiliation: Complex Neural Systems, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Room 748, Montréal, QC, Canada H3A 2B4.
authors.forename: J-S
authors.initials: JS
authors.lastname: Aucoin
authors.forename: P
authors.initials: P
authors.lastname: Jiang
authors.forename: N
authors.initials: N
authors.lastname: Aznavour
authors.forename: X-K
authors.initials: XK
authors.lastname: Tong
authors.forename: M
authors.initials: M
authors.lastname: Buttini
authors.forename: L
authors.initials: L
authors.lastname: Descarries
authors.forename: E
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000344:Afferent Pathways / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000378:metabolism / Q000473:pathology*; D003714:Denervation; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology; D017729:Presynaptic Terminals / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014855:Wallerian Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D012701:Serotonin; C002744:3-nitrotyrosine; D014443:Tyrosine; D013482:Superoxide Dismutase; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine