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Alzheimer Dis Assoc Disord. 2007 Oct-Dec;21(4):276-91.

Oxidative stress and transcriptional regulation in Alzheimer disease.

Author information

1
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Burke Medical Research Institute, White Plains, NY 10605, USA. qis2002@med.cornell.edu

Abstract

Alzheimer disease (AD) is defined by progressive impairments in memory and cognition and by the presence of extracellular neuritic plaques and intracellular neurofibrillary tangles. However, oxidative stress and impaired mitochondrial function always accompany AD. Mitochondria are a major site of production of free radicals [ie, reactive oxygen species (ROS)] and primary targets of ROS. ROS are cytotoxic, and evidence of ROS-induced damage to cell membranes, proteins, and DNA in AD is overwhelming. Nevertheless, therapies based on antioxidants have been disappointing. Thus, alternative strategies are necessary. ROS also act as signaling molecules including for transcription. Thus, chronic exposure to ROS in AD could activate cascades of genes. Although initially protective, prolonged activation may be damaging. Thus, therapeutic approaches based on modulation of these gene cascades may lead to effective therapies. Genes involved in several pathways including antioxidant defense, detoxification, inflammation, etc, are induced in response to oxidative stress and in AD. However, genes that are associated with energy metabolism, which is necessary for normal brain function, are mostly down-regulated. Redox-sensitive transcription factors such as activator protein-1, nuclear factor-kappaB, specificity protein-1, and hypoxia-inducible factor are important in redox-dependent gene regulation. Peroxisome proliferators-activated receptor-gamma coactivator (PGC-1alpha) is a coactivator of several transcription factors and is a potent stimulator of mitochondrial biogenesis and respiration. Down-regulated expression of PGC-1alpha has been implicated in Huntington disease and in several Huntington disease animal models. PGC-1alpha role in regulation of ROS metabolism makes it a potential candidate player between ROS, mitochondria, and neurodegenerative diseases. This review summarizes the current progress on how oxidative stress regulates the expression of genes that might contribute to AD pathophysiology and the implications of the transcriptional modifications for AD. Finally, potential therapeutic strategies based on the updated understandings of redox state-dependent gene regulation in AD are proposed to overcome the lack of efficacy of antioxidant therapies.

PMID:
18090434
PMCID:
PMC3109432
DOI:
10.1097/WAD.0b013e31815721c3
[Indexed for MEDLINE]
Free PMC Article
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