Altered ryanodine receptor expression in mild cognitive impairment and Alzheimer's disease

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• 作者：Angela M. Bruno^a ; Jeff Y. Huang^a ; David A. Bennett^b ; ^c ; Robert A. Marr^a ; Michelle L. Hastings^d ; ^{Michelle.hastings@rosalindfranklin.edu} ; Grace E. Stutzmann^a
• 关键词：Alternative splicing ; Alzheimer's disease ; Apoptosis ; Calcium ; Endoplasmic reticulum ; Mild cognitive impairment ; Pre-mRNA splicing ; Ryanodine receptor
• 刊名：Neurobiology of Aging
• 出版年：2012
• 期刊代码：202_01974580
• 类别：med
• 出版时间：May, 2012
• 卷：33
• 期：5
• 页码：1001.e1-1001.e6
• 文件大小：996 K

摘要

Intracellular Ca²⁺ dysregulation is an underlying component of Alzheimer's disease (AD) pathophysiology, and recent evidence implicates the ryanodine receptor (RyR) in the disease pathway. Three genes code for different RyR isoforms and each gene transcript gives rise to several alternatively spliced messenger RNAs (mRNAs). These variants confer distinct functionality to the RyR channel, such as altering Ca²⁺ release properties or subcellular localization. Changes in RyR isoform expression and alternative splicing have not been examined for potential roles in AD pathogenesis. Here, we compare mRNA levels of the RyR2 and RyR3 isoforms as well as specific alternatively spliced variants across vulnerable brain regions from postmortem samples of individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. We find an increase in RyR2 transcripts in MCI brains compared with no cognitive impairment. In addition, there is a reduction in a RyR2 splice variant, associated with an antiapoptotic function, in MCI and AD brains. These alterations in RyR expression at early disease stages may reflect the onset of pathologic mechanisms leading to later neurodegeneration.