期刊
JOURNAL OF NEUROSCIENCE RESEARCH
卷 98, 期 10, 页码 1905-1932出版社
WILEY
DOI: 10.1002/jnr.24672
关键词
Alzheimer's disease; amyloid; dementia; myelin; oligodendrocyte; RRID; AB_91939; RRID; AB_476692; RRID; AB_570666; RRID; AB_662798; RRID; AB_162542; RRID; AB_2040202; RRID; AB_2236897; RRID; AB_2493179; RRID; AB_2534017; RRID; AB_2534117; RRID; AB_2535792; RRID; AB_2535794; RRID; AB_2535864; RRID; AB_2536183; RRID; AB_2617137; RRID; AB_2827931; RRID; AB_10013361; RRID; AB_10806491; RRID; IMSR_JAX; 006148; RRID; IMSR_JAX; 007669; RRID; IMSR_JAX; 008169; RRID; MMRRC_034836-JAX; RRID; SCR_000441; RRID; SCR_002798; RRID; SCR_003070; RRID; SCR_011323
资金
- Alzheimer's Society UK
- BUPA Foundation [22095098]
- National Health and Medical Research Council [1030939, 1045240, 1066025, 1077792, 1139180]
- Multiple Sclerosis Research Australia [11014, 15-054]
- Penn Foundation
- Macquarie Group Foundation
- Brain Foundation
- Dementia Australia Research Foundation Postgraduate Research Scholarship
- Tasmanian Graduate Research and Menzies Institute for Medical Research Scholarship
- National Health and Medical Research Council of Australia [1139180, 1077792, 1066025] Funding Source: NHMRC
In Alzheimer's disease, amyloid plaque formation is associated with the focal death of oligodendrocytes and soluble amyloid beta impairs the survival of oligodendrocytes in vitro. However, the response of oligodendrocyte progenitor cells (OPCs) to early amyloid pathology remains unclear. To explore this, we performed a histological, electrophysiological, and behavioral characterization of transgenic mice expressing a pathological form of humanamyloid precursor protein(APP), containing three single point mutations associated with the development of familial Alzheimer's disease (PDGFB-APP(Sw.Ind), also known as J20 mice).PDGFB-APP(Sw.Ind)transgenic mice had impaired survival from weaning, were hyperactive by 2 months of age, and developed amyloid plaques by 6 months of age, however, their spatial memory remained intact over this time course. Hippocampal OPC density was normal in P60-P180PDGFB-APP(Sw.Ind)transgenic mice and, by performing whole-cell patch-clamp electrophysiology, we found that their membrane properties, including their response to kainate (100 mu M), were largely normal. However, by P100, the response of hippocampal OPCs to GABA was elevated inPDGFB-APP(Sw.Ind)transgenic mice. We also found that the nodes of Ranvier were shorter, the paranodes longer, and the myelin thicker for hippocampal axons in young adultPDGFB-APP(Sw.Ind)transgenic mice compared with wildtype littermates. Additionally, oligodendrogenesis was normal in young adulthood, but increased in the hippocampus, entorhinal cortex, and fimbria ofPDGFB-APP(Sw.Ind)transgenic mice as pathology developed. As the new oligodendrocytes were not associated with a change in total oligodendrocyte number, these cells are likely required for cell replacement.
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