Cholinergic neuropathology in a mouse model of Alzheimer's disease

Transgenic mice over-expressing mutant human amyloid precursor protein (PDAPP mouse) develop several Alzheimer’s disease (AD)-like lesions including an age-related accumulation of amyloid-?-containing neuritic plaques. Although aged, heterozygous PDAPP mice also exhibit synaptic and glial cell changes, that is characteristic of AD pathology, no evidence of neurodegeneration has been observed. The present study sought to determine whether homozygous PDAPP mice, which express very high levels of amyloid-? peptide, exhibit AD-like cholinergic degenerative changes, and whether the changes paralleled the deposition of amyloid-? plaques. Mice were examined at months 2 and 4 and years 1 and 2 of their age. There was an age-related increase in the density of amyloid-??plaques in the cortex and hippocampus of the PDAPP animals, but at months 2 and 4, there were very few plaques. There was also an age-related reduction in the density of cholinergic nerve terminals in the cerebral cortex (as early as 4-months of age), there were over a 50% reduction at year 2, and a 15% reduction in the number of basal forebrain cholinergic somata, which innervate the cerebral cortex and hippocampus. These data indicate that the homozygous PDAPP mouse exhibits cholinergic degenerative pathology similar to that observed in AD, and the neurodegenerative changes occur prior to the deposition of amyloid-?- containing neuritic plaques.