期刊
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
卷 72, 期 4, 页码 272-285出版社
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0b013e318288a8dd
关键词
beta-amyloid; Alzheimer disease; Basal forebrain; Cholinergic system; Murine p75(NTR) saporin; Senile plaques
资金
- ISCIII-Subdireccion General de Evaluacion y Fomento de la Investigacion [PS09/00969]
- Junta de Andalucia, Proyectos de Excelencia [P11-CTS-7847]
- Instituto de Salud Carlos III
- FEDER (European Union)
- Fondo Europeo de Desarrollo Regional Una manera de hacer Europa [PI12/00675]
- NIH [R01 EB000768, R00 AG033670]
- [RYC-2008-02333]
Although extensive evidence supports the role of beta-amyloid (A beta) in Alzheimer disease (AD), the neurotoxic mechanisms underlying AD pathogenesis are not understood. On the other hand, neuronal loss is the pathologic feature that best correlates with cognitive impairment. We hypothesized that cholinergic neurodegeneration may lead to A beta deposition and tested this by inducing selective cholinergic lesions in APPswe/PS1dE9 mice with murine p75(NTR) saporin (mu p75-SAP). Intracerebroventricular lesions that removed approximately 50% of cholinergic innervation to the cortex and hippocampus were induced in animals with incipient (similar to 3 months) and marked (similar to 7 months of age) A beta deposition. Cranial windows were implanted, and A beta deposition was monitored in vivo using multiphoton microscopy. Deposition of A beta was increased as soon as 7 days after the lesion, and this effect was maintained up to 3 months later. Postmortem studies using immunohistochemistry with an anti-A beta antibody corroborated these findings in both cerebral cortex and hippocampus. Tau phosphorylation was also significantly increased after the lesions. Cholinergic denervation resulted in early memory impairment at 3 months of age that worsened with age (similar to 7 months); there was a synergistic effect between cholinergic denervation and the presence of APP/PS1 transgenes. Altogether, our data suggest that cholinergic denervation may trigger A beta deposition and synergistically contribute to cognitive impairment in AD patients.
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