Ultrastructural and behavioural changes precede amyloid deposition in a transgenic model of Alzheimer's disease

被引:76
作者
Richardson, JC
Kendal, CE
Anderson, R
Priest, F
Gower, E
Soden, P
Gray, R
Topps, S
Howlett, DR
Lavender, D
Clarke, NJ
Barnes, JC
Haworth, R
Stewart, MG
Rupniak, HTR
机构
[1] GlaxoSmithKline, Neurol Ctr Excellence Drug Discov, Harlow CM19 5AW, Essex, England
[2] Glaxo Wellcome Res & Dev Ltd, Med Sci Res Ctr, Previous Comparat Pathol Dept, Stevenage SG1 2NY, Herts, England
[3] Open Univ, Dept Sci Biol, Milton Keynes MK7 6AA, Bucks, England
[4] GlaxoSmithKline, Dept Pathol, Ware SG12 0DP, Herts, England
关键词
cognition; dementia; electron microscopy; dystrophic neurites;
D O I
10.1016/S0306-4522(03)00389-0
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
We describe the thorough characterisation of a new transgenic mouse line overexpressing the 695-amino acid isoform of human amyloid precursor protein harbouring the Swedish double familial Alzheimer's disease mutation. This line, referred to as TAS10, exhibits neuropathological features and cognitive deficits that are closely correlated to the accumulation of Abeta in their brain and that are reminiscent of those observed in AD. Data on the TAS10 line are presented at five time points: 2, 6, 12, 18 and 24 months in a longitudinal study. The TAS10 line is characterised by the following changes: i) significant age-related increases in the levels of total and individual species (1-40, 1-42) of beta-amyloid in the brains of transgenics compared with non-transgenic littermates; ii) transgenic mice showed pronounced spatial learning deficits in the Morris water maze at 6 months and working memory deficits by 12 months; iii) amyloid plaque and associated pathologies were observed by the 12-month time point and the burden increased substantially, particularly in the cortex, by 18 months; iv) electron microscopy of the hippocampus of transgenic mice showed evidence of abnormal ultrastructural features such as dystrophic neurites and lipid deposits that developed from 6 months and increased in number and severity with age. Morphometric studies demonstrate that the synapse to neuron ratio is higher in transgenics than in control mice at 12 months, but this ratio decreases as they age and synapse size increases. Thus, this mouse model exhibits a close correlation of amyloid burden with behavioural deficits and ultrastructural abnormalities and so represents an ideal system to study the mechanisms underlying the impact of amyloid pathology on CNS function. (C) 2003 IBRO. Published by Elsevier Ltd. All rights reserved.
引用
收藏
页码:213 / 228
页数:16
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