Acetylcholinesterase-positive fiber deafferentation and cell shrinkage in the septohippocampal pathway of aged amyloid precursor protein London mutant transgenic mice

Several lines of evidence implicate a cholinergic deficit in Alzheimer's di sease (AD). Transgenic mice that overexpress clinical mutants of the human amyloid precursor protein (APP) have been generated that recapitulate many aspects of AD. We now analyzed the cholinergic system in aged APP/London tr ansgenic mice. The major finding was the reorganization of acetylcholineste rase-positive fibers within the hippocampus and the reduced size of choline rgic cells in the medial septum. The reduction of acetylcholinesterase-posi tive fibers in the subiculum together with increased fiber density in the C A1 and in the dentate gyrus suggests a synaptic sprouting compensatory mech anism within the hippocampus. In the cortex, amyloid plaques were associate d with intense acetylcholinesterase activity and surrounded by dystrophic a cetylcholinesterase-positive fibers. Nevertheless, the overall pattern of c holinergic innervation was unchanged. These results demonstrate that overex pression of APP/London caused, besides amyloid plaques in aged mouse brain, also cholinergic deafferentation and cholinergic cell shrinkage. (C) 2000 Academic Press.