A specific amyloid-β protein assembly in the brain impairs memory

被引：2302

作者：

Sylvain Lesné ^{[1
]}

Ming Teng Koh ^{[4
]}

Linda Kotilinek ^{[1
]}

Rakez Kayed ^{[6
]}

Charles G. Glabe ^{[6
]}

Austin Yang ^{[7
]}

Michela Gallagher ^{[4
]}

Karen H. Ashe ^{[1
]}

机构：

[1] Department of Neurology, University of Minnesota Medical School, Minneapolis

[2] Department of Neuroscience, University of Minnesota Medical School, Minneapolis

[3] Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis

[4] Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore

[5] Geriatric Research Education Clinical Center, Minneapolis VA Medical Center, Minneapolis

[6] Department of Molecular Biology and Biochemistry, University of California, Irvine

[7] Department of Pharmaceutical Sciences, University of Southern California, Los Angeles

来源：

Nature | 2006年 / 440卷 / 7082期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1038/nature04533

中图分类号：

学科分类号：

摘要：

Memory function often declines with age1, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons2. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-β precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-β protein amyloidosis. Young Tg2576 mice (<6 months old) have normal memory and lack neuropathology, middle-aged mice (6-14 months old) develop memory deficits without neuronal loss, and old mice (>14 months old) form abundant neuritic plaques containing amyloid-β (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-β assembly, which we term Aβ*56 (Aβ star 56). Aβ*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Aβ*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease. © 2006 Nature Publishing Group.

引用

页码：352 / 357

页数：5

共 28 条

[1] Craik F.I., Handbook of the Psychology of Aging, pp. 384-420, (1977)
[2] Morrison J.H., Hof P.R., Life and death of neurons in the aging brain, Science, 278, pp. 412-419, (1997)
[3] Hsiao K., Et al., Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice, Science, 274, pp. 99-102, (1996)
[4] Irizarry M.C., McNamara M., Fedorchak K., Hsiao K., Hyman B.T., APPSW transgenic mice develop age-related Aβ deposits and neuropil abnormalities, but no neuronal loss in CA1, J. Neuropathol. Exp. Neurol., 56, pp. 965-973, (1997)
[5] Kawarabayashi T., Et al., Age-dependent changes in brain, CSF, and plasma amyloid β protein in the Tg2576 transgenic mouse model of Alzheimer's disease, J. Neurosci., 21, pp. 372-381, (2001)
[6] Westerman M.A., Et al., The relationship between Aβ and memory in the Tg2576 mouse model of Alzheimer's disease, J. Neurosci., 22, pp. 1858-1867, (2002)
[7] Kawas C.H., Et al., Visual memory predicts Alzheimer's disease more than a decade before diagnosis, Neurology, 60, pp. 1089-1093, (2003)
[8] Small G.W., Et al., Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease, Proc. Natl Acad. Sci. USA, 97, pp. 6037-6042, (2000)
[9] Bookheimer S.Y., Et al., Patterns of brain activation in people at risk for Alzheimer's disease, N. Engl. J. Med., 343, pp. 450-456, (2000)
[10] Albert M.S., Memory decline: The boundary between aging and age-related disease, Ann. Neurol., 51, pp. 282-284, (2002)

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