Cholinergic neuropathology in a mouse model of Alzheimer's disease.
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.
German
Dwight C
DC
Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, Texas 75390-9070, USA. dwight.german@utsouthwestern.edu
Yazdani
Umar
U
Speciale
Samuel G
SG
Pasbakhsh
Parichehr
P
Games
Dora
D
Liang
Chang-Lin
CL
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
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine