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

• Published in: Neurobiology of aging Vol. 33; no. 5; pp. 1001.e1 - 1001.e6
• Main Authors: Bruno, Angela M, Huang, Jeff Y, Bennett, David A, Marr, Robert A, Hastings, Michelle L, Stutzmann, Grace E
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2012
• Subjects: Aged; Aged, 80 and over; Aging; Alternative splicing; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Apoptosis; Brain; Calcium; Calcium (intracellular); Cognitive ability; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; Endoplasmic reticulum; Female; Humans; Internal Medicine; Male; Mild cognitive impairment; mRNA; Nervous system; Neurodegenerative diseases; Neurology; Pre-mRNA splicing; Ryanodine receptor; Ryanodine Receptor Calcium Release Channel - adverse effects; Ryanodine Receptor Calcium Release Channel - biosynthesis; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine receptors; Transcription; Alternative splicing; Calcium; Mild cognitive impairment; Ryanodine receptor; Pre-mRNA splicing; Alzheimer's disease; Endoplasmic reticulum; Apoptosis
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2011.03.011

Abstract 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.