P1‐070: Absence of α7 nicotinic acetylcholine receptors (α7nAChR) improve cognitive deficits and dendritic pathology in a mouse model of Alzheimer's disease (AD)

It has been recently shown that β-amyloid1–42, binds to α7nAChR with high affinity and they are both found co-localized in neuritic plaques of human brains with AD (Wang et al, J Biological Chem., 2000, 275:5626). To address the question whether α7nAChR play a role in the pathophysiology of AD we used transgenic mice over-expressing a familial AD mutated form of the human amyloid precursor protein (APP) (Hsia et al, PNAS, 1999, 96:3228) on the background of a knock-out (KO) for the α7nAChR (Paylor et al, Learning & Memory, 1998, 5:302). The experimental group and control littermates for this experiment were as follows: APP+/α7KO; APP+; wildtype (WT) and α7KO. The animals were tested in a battery of behavioral tasks with special interest in learning and memory and the brains were processed postmortem to study neuropathological features. Compared with WT or α7KO, 13–16 months old APP+ mice are impaired in finding an escape platform in the Morris Water Maze Test in both, visible and hidden versions of the test, despite normal visual ability. The deficit in the acquisition of this learning and memory task is rescued in mice with a KO of the α7nAChR gene since APP+/α7KO mice were able to localize the platform in a similar way as WT and α7KO control groups. Neuropathological analysis in hippocampus and frontal cortex showed a significant 20% reduction in dendritic density in the APP+ mice that was significantly reversed in the APP+/α7KO mice. Furthermore, a significant increase in frontal cortex gliosis was observed in APP+ mice that was absent in the APP+/α7KO group and the same trend for gliosis was seen in the hippocampus although this result did not reach statistical significance. These results are even more striking by the fact that levels of β-amyloid and amyloid plaques were not different between APP+ and APP+/α7KO mice. Taken together, these results predict that blocking α7nAChR might protect against neurodegeneration and cognitive decline induced by β-amyloid. Further characterization of this novel mice model of slowed AD is in progress. Funded by: NIH grant #5 P01 AG010435–16.