Expression of Nrf2 in Neurodegenerative Diseases

• Published in: Journal of neuropathology and experimental neurology Vol. 66; no. 1; pp. 75 - 85
• Main Authors: Ramsey, Chenere P, Glass, Charles A, Montgomery, Marshall B, Lindl, Kathryn A, Ritson, Gillian P, Chia, Luis A, Hamilton, Ronald L, Chu, Charleen T, Jordan-Sciutto, Kelly L
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.01.2007; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Aged; Aged, 80 and over; Biological and medical sciences; Case-Control Studies; Cell Nucleus - metabolism; Cytoplasm - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Gene Expression - physiology; Glial Fibrillary Acidic Protein - metabolism; Hippocampus - metabolism; Hippocampus - pathology; Humans; Immunohistochemistry - methods; Medical sciences; Microscopy, Confocal - methods; Middle Aged; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurodegenerative Diseases - physiopathology; Neurology; Neurons - metabolism; Neurons - pathology; NF-E2-Related Factor 2 - metabolism; Postmortem Changes; Substantia Nigra - metabolism; Substantia Nigra - pathology; Tumors of the nervous system. Phacomatoses; Oxidative stress; Brain; Nervous system diseases; Neuron; Transcription; Neurodegeneration; Central nervous system; Degenerative disease; Antioxidant; Encephalon
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/nen.0b013e31802d6da9

In response to oxidative stress, the nuclear factor E2-related factor 2 (Nrf2) transcription factor translocates from the cytoplasm into the nucleus and transactivates expression of genes with antioxidant activity. Despite this cellular mechanism, oxidative damage is abundant in Alzheimer and Parkinson disease (AD and PD). To investigate mechanisms by which Nrf2 activity may be aberrant or insufficient in neurodegenerative conditions, we assessed Nrf2 localization in affected brain regions of AD, Lewy body variant of AD (LBVAD), and PD. By immunohistochemistry, Nrf2 is expressed in both the nucleus and the cytoplasm of neurons in normal hippocampi with predominant expression in the nucleus. In AD and LBVAD, Nrf2 was predominantly cytoplasmic in hippocampal neurons and was not a major component of beta amyloid plaques or neurofibrillary tangles. By immunoblotting, we observed a significant decrease in nuclear Nrf2 levels in AD cases. In contrast, Nrf2 was strongly nuclear in PD nigral neurons but cytoplasmic in substantia nigra of normal, AD, and LBVAD cases. These findings suggest that Nrf2-mediated transcription is not induced in neurons in AD despite the presence of oxidative stress. In PD, nuclear localization of Nrf2 is strongly induced, but this response may be insufficient to protect neurons from degeneration.