期刊
NEUROBIOLOGY OF AGING
卷 68, 期 -, 页码 123-133出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2018.02.025
关键词
Alzheimer's disease; beta-amyloid; Synaptic plasticity; Noradrenaline; Oxidative stress; Patch-clamp recordings
资金
- Bank of Italy [744460/13]
Numerous studies indicate that the cerebellum undergoes structural and functional neurodegenerative changes in Alzheimer's disease. The purpose of this study was to examine the extent of cerebellar alterations at early, preplaque stage of the pathology in TgCRND8 mice through behavioral, electrophysiological, and molecular analysis. Balance beam test and foot-printing analysis revealed significant motor coordination and balance deficits in 2-month-old TgCRND8 mice compared to their littermates. Patch-clamp recordings performed on cerebellar slices of transgenic mice showed synaptic plasticity deficit and loss of noradrenergic modulation at parallel fiber-Purkinje cell synapse suggesting an early dysfunction of the cerebellar circuitry due to amyloid precursor protein overexpression. Finally, western blot analysis revealed an enhanced expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p47(phox) and p67(phox) as well as Ca2+/calmodulin-dependent protein kinase and protein kinase C alpha in the cerebellum of 2-month-old transgenic mice. Therefore, we propose the existence of self-sustaining feedback loop involving the formyl peptide receptor 2-reactive oxygen species-Ca2+/calmodulin-dependent protein kinase II-protein kinase C alpha pathway that may promote reactive oxygen species generation in the early stage of Alzheimer's disease and eventually contribute to the exacerbation of pathological phenotype. (C) 2018 Elsevier Inc. All rights reserved.
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