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The Journal of Neuroscience, October 5, 2005, 25(40):9171-9175; doi:10.1523/JNEUROSCI.3040-05.2005

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BRIEF COMMUNICATION
Ribosome Dysfunction Is an Early Event in Alzheimer's Disease

Qunxing Ding,¹ William R. Markesbery,^2,3 Qinghua Chen,³ Feng Li,³ and Jeffrey N. Keller^1,3

Departments of ¹Anatomy and Neurobiology and ²Pathology and Neurology and ³Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536-0230

Alzheimer's disease (AD) is a progressive and devastating disorder that is often preceded by mild cognitive impairment (MCI). In the present study, we report that in multiple cortical areas of MCI and AD subjects, there is a significant impairment in ribosome function that is not observed in the cerebellum of the same subjects. The impairment in ribosome function is associated with a decreased rate and capacity for protein synthesis, decreased ribosomal RNA and tRNA levels, and increased RNA oxidation. No alteration in the level of initiation factors was observed in the brain regions exhibiting impairments in protein synthesis. Together, these data indicate for the first time that impairments in protein synthesis may be one of the earliest neurochemical alterations in AD and directly demonstrate that the polyribosome complex is adversely affected early in the development of AD. These data have important implications for AD studies involving proteomics and studies analyzing proteolysis in AD, indicate that oxidative damage may contribute to decreased protein synthesis, and suggest a role for alterations in protein synthesis as a novel contributor to the onset and development of AD.

Key words: Alzheimer's disease; mild cognitive impairment; oxidative stress; protein synthesis; ribosome; tRNA; rRNA

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Received March 20, 2005; revised August 11, 2005; accepted August 13, 2005.

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