title: Cholinergic neuropathology in a mouse model of Alzheimer's disease.
abstract: Transgenic mice overexpressing mutant human amyloid precursor protein (PDAPP mice) develop several Alzheimer's disease (AD)-like lesions including an age-related accumulation of amyloid-beta (Abeta)-containing neuritic plaques. Although aged, heterozygous PDAPP mice also exhibit synaptic and glial cell changes characteristic of AD pathology, no evidence of widespread neuronal loss has been observed. The present study sought to determine whether homozygous PDAPP mice, which express very high levels of Abeta peptide, exhibit AD-like cholinergic degenerative changes, and whether the changes parallel the deposition of Abeta plaques. Mice were examined at 2 and 4 months and at 1 and 2 years of age. There was an age-related increase in the density of Abeta plaques in the cortex and hippocampus of the PDAPP animals; at 4 months of age there were very few plaques, and at 2 years there was a very high density of plaques. There was an age-related reduction in the density of cholinergic nerve terminals in the cerebral cortex; at 2 months there was a normal density of nerve terminals, but as early as age 4 months there was an approximately 50% reduction. However, at age 2 years there was no difference in the number or size of basal forebrain cholinergic somata compared with 2-month-old PDAPP mice. These data indicated that the homozygous PDAPP mouse exhibits cholinergic nerve terminal degenerative pathology and that the cortical neurodegenerative changes occur before the deposition of Abeta-containing neuritic plaques.
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, Texas 75390-9070, USA. dwight.german@utsouthwestern.edu
authors.forename: Dwight C
authors.initials: DC
authors.lastname: German
authors.forename: Umar
authors.initials: U
authors.lastname: Yazdani
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Speciale
authors.forename: Parichehr
authors.initials: P
authors.lastname: Pasbakhsh
authors.forename: Dora
authors.initials: D
authors.lastname: Games
authors.forename: Chang-Lin
authors.initials: CL
authors.lastname: Liang
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000367:Age Factors; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000032:analysis / Q000378:metabolism; D002799:Cholinergic Fibers / Q000473:pathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000473:pathology*; D017729:Presynaptic Terminals / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine