Memory impairment and cholinergic dysfunction by centrally administered Aβ and carboxyl-terminal fragment of Alzheimer's APP in mice

Alzheimer's disease (AD) is characterized by cognitive impairment and excessive deposition of neurite plaques (NPs). Although the pathogenic mechanism of AD is not exactly known, there is increasing evidence that amyloid beta protein (A beta), which is the major constituent of NPs and is derived from amyloid precursor protein (APP), plays a key role in the neuronal degeneration in AD. However, because there are several discrepancies between A beta deposition and neurodegeneration or cognitive impairment in AD, the possible effects of other cleavage products of APP need to be explored. We previously showed that a recombinant carboxyl-terminal 105 amino acid fragment of APP (CT105) induced neurotoxicities both in vitro and in vivo. However, it is unclear whether learning and memory impairments and neurochemical changes are induced by CT105. To elucidate the in vivo neurotoxicities of A beta and CT105, we examined behavioral changes using a Y-maze and a water maze task following a single intracerebroventricular injection of CT105 (68.5, 342 and 685 pmol) or A beta (1-42) (685 pmol) to mice. We also quantified the changes in the acetylcholine (ACh) level and assayed mitochondrial pyruvate dehydrogenase (PDH) activity. CT105 caused much more significant impairments in cued, spatial, and working memory performances of mice in Y-maze and water maze tasks in a dose-dependent manner than A beta (1-42). Also, the mice injected with CT105 revealed significant decreases in ACh levels and reduced PDH activities in the cerebral cortex and hippocampus compared with the saline-treated control and A beta (1-42)-treated groups. These results suggest that learning and memory impairment induced by centrally administered CT105 is in some way related to the reduced ACh levels and mitochondrial PDH activities and that CT105 is more potent than A beta in inducing cognitive dysfunction.