TY - JOUR
T1 - Epigenetic changes in Alzheimer's disease
T2 - Decrements in DNA methylation
AU - Mastroeni, Diego
AU - Grover, Andrew
AU - Delvaux, Elaine
AU - Whiteside, Charisse
AU - Coleman, Paul D.
AU - Rogers, Joseph
N1 - Funding Information:
This research was supported by NIA AGO-7367 (JR), NIA 030429 (PC), and by the Arizona Alzheimer's Research Consortium (JR/PC). We thank Dr. Thomas Beach, Lucia Sue, and their staff for provision of tissue samples and postmortem evaluations, and Dr. Marwan Sabbagh and his staff for antemortem neurologic evaluations and diagnoses.
PY - 2010/12
Y1 - 2010/12
N2 - DNA methylation is a vital component of the epigenetic machinery that orchestrates changes in multiple genes and helps regulate gene expression in all known vertebrates. We evaluated immunoreactivity for two markers of DNA methylation and eight methylation maintenance factors in entorhinal cortex layer II, a region exhibiting substantial Alzheimer's disease (AD) pathology in which expression changes have been reported for a wide variety of genes. We show, for the first time, neuronal immunoreactivity for all 10 of the epigenetic markers and factors, with highly significant decrements in AD cases. These decrements were particularly marked in PHF1/PS396 immunoreactive, neurofibrillary tangle-bearing neurons. In addition, two of the DNA methylation maintenance factors, DNMT1 and MBD2, have been reported also to interact with ribosomal RNAs and ribosome synthesis. Consistent with these findings, DNMT1 and MBD2, as well as p66α, exhibited punctate cytoplasmic immunoreactivity that co-localized with the ribosome markers RPL26 and 5.8. s rRNA in ND neurons. By contrast, AD neurons generally lacked such staining, and there was a qualitative decrease in RPL26 and 5.8. s rRNA immunoreactivity. Collectively, these findings suggest epigenetic dysfunction in AD-vulnerable neurons.
AB - DNA methylation is a vital component of the epigenetic machinery that orchestrates changes in multiple genes and helps regulate gene expression in all known vertebrates. We evaluated immunoreactivity for two markers of DNA methylation and eight methylation maintenance factors in entorhinal cortex layer II, a region exhibiting substantial Alzheimer's disease (AD) pathology in which expression changes have been reported for a wide variety of genes. We show, for the first time, neuronal immunoreactivity for all 10 of the epigenetic markers and factors, with highly significant decrements in AD cases. These decrements were particularly marked in PHF1/PS396 immunoreactive, neurofibrillary tangle-bearing neurons. In addition, two of the DNA methylation maintenance factors, DNMT1 and MBD2, have been reported also to interact with ribosomal RNAs and ribosome synthesis. Consistent with these findings, DNMT1 and MBD2, as well as p66α, exhibited punctate cytoplasmic immunoreactivity that co-localized with the ribosome markers RPL26 and 5.8. s rRNA in ND neurons. By contrast, AD neurons generally lacked such staining, and there was a qualitative decrease in RPL26 and 5.8. s rRNA immunoreactivity. Collectively, these findings suggest epigenetic dysfunction in AD-vulnerable neurons.
KW - Alzheimer's disease
KW - DNA methylation
KW - Epigenetics
KW - Neuron
KW - Ribosome
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U2 - 10.1016/j.neurobiolaging.2008.12.005
DO - 10.1016/j.neurobiolaging.2008.12.005
M3 - Article
C2 - 19117641
AN - SCOPUS:78650179659
SN - 0197-4580
VL - 31
SP - 2025
EP - 2037
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 12
ER -