Selective cholinergic denervation, independent from oxidative stress, in a mouse model of Alzheimer’s disease
Section snippets
Animals
Experiments were approved by the Animal Ethics Committee of the respective institutions, and abided by the guidelines of the Canadian or American Council for Animal Care aimed at minimizing the number of animals used and their suffering. We used hAPP transgenic mice overexpressing the FAD-linked mutations hAPPSw,Ind carrying the 670/671KM→NL (Sw) double mutation and the 717V→F mutation (Ind; line J20; Mucke et al., 2000). Mice were screened for transgene expression by Touchdown PCR with
ACh and 5-HT innervations in wild-type mouse hippocampus and parietal cortex
In keeping with earlier reports in mouse (Wong et al 1999, Aznavour et al 2002), fine varicose ChAT-immunostained fibers pervaded all layers of the dorsal hippocampus and parietal cortex, as illustrated here in an 18 month-old wild-type mouse (Fig. 2A, C). ChAT-positive cell bodies were rare in hippocampus (not shown), and the overall regional density of the ACh innervation was comparable (15–20 m of axons per mm3 of tissue) between CA1, CA3 and DG (Fig. 2A; see Fig. 4, Fig. 5, Fig. 6). In
Early and non-selective neurotoxicity of Aβ plaques in the hAPPSw,Ind mouse
A first finding of this study was that neuritic plaques, as soon as they appeared, were locally neurotoxic to both ACh and 5-HT axons in hAPPSw,Ind mouse brain. This was evidenced by the presence of swollen and distorted ChAT- and 5-HT-immunostained axons in the vicinity or within the core of plaques in 6 month-old mice, an age at which the plaques were still rare and minuscule, and when there was no measurable denervation. This clearly indicates that aggregated Aβ species exert a local,
Conclusions
Our study shows that the plaque-associated, non-selective neurodegeneration and the diffuse, selective ACh denervation detected here in hAPPSw,Ind transgenic mice are independent events, most likely secondary to increased levels of aggregated and soluble forms of Aβ peptides, respectively. Our results also indicate that oxidative stress is not a primary factor in the diffuse ACh deficit. In view of the selectivity and regional progression of this ACh denervation in hippocampus, and later
Acknowledgments
We thank Dr. L. Mucke (Gladstone Inst of Neurological Disease and Dept of Neurology, UCSF, CA, USA) for the hAPPSw,Ind transgenic mouse breeders, and Drs. C. Cozzari (Rome, Italy) and B. K. Hartman (Minneapolis, MN, USA) for their generous gift of monoclonal anti-ChAT antibody. We are also grateful to Mrs. N. Serluca and A. Yanes for technical support, Drs. T. Yeo and F. Longo (VA San Francisco Medical Center and Dept of Neurology, UCSF) for help with the ChAT assay, and Ms L. Michel for
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