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O2–07–04: Genetic ablation of Nrf2 modulates Alzheimer's disease–like pathology in APP/PS1 mouse
Author(s) -
Joshi Gururaj,
Gan KokAnn,
Everson Joshua,
Johnson Jeffrey
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.04.174
Subject(s) - genetically modified mouse , oxidative stress , hippocampus , gene knockin , presenilin , amyloid precursor protein , p3 peptide , hippocampal formation , biology , pathology , cerebellum , transgene , microbiology and biotechnology , chemistry , alzheimer's disease , endocrinology , biochemistry , medicine , gene , disease
Background: The major pathological hallmarks of Alzheimer’s disease (AD) are presence of beta-amyloid plaques surrounded by dead neurites and neurofibrillary tangles. AD brain is under tremendous oxidative stress that may be a cause or consequence of the pathology. The major familial AD-linked mutations are the mutations in amyloid precursor protein (APP) and Presinilin 1 and 2 (PS1 and 2). The most well-known mouse model to study AD is the mouse carrying human APPswe and PS1DE9 mutation (APP/PS1 mouse). These mice show accelerated plaque deposition. The transcription factor Nrf2 is the primary cellular defense factor against cytotoxic effects of oxidative stress. It is sequestered in the cytoplasm by Keap1 and translocate to nucleus upon oxidative insult to transcribe phase II detoxification genes. Methods: The transgenic mice were developed by crossing Nrf2 knock out (Nrf2-/-) mice to APP/PS1 mouse. The cortex, hippocampus and cerebellum were harvested from 7 mo mice for biochemistry and molecular biology. Brains were harvested for histology. Results: We observed changes in detergent soluble and urea soluble beta-amyloid levels in APP/PS1/Nrf2-/mice compared to APP/PS1/Nrf2+/+ mice. A significant decrease in total p62 levels was observed in cortex and hippocampus of APP/PS1/Nrf2-/mice compared to APP/PS1/Nrf2+/+mice. A further investigation into soluble and insoluble fraction from hippocampal tissue for p62 protein expression revealedmodulation of p62 level in APP/PS1/Nrf2-/compared to APP/PS1/Nrf2+/+ mice. There were altered poly-ubiquitin conjugated proteins levels in APP/PS1/Nrf2-/cortex and hippocampus tissue compared to APP/PS1/Nrf2+/+ mice. Conclusions: SQSTM1/p62 regulates autophagic removal of ubiquitinated protein aggregates. Others have showed induction of the p62 gene by oxidative stress, which is mediated by Nrf2. In APP/PS1 mice an increase in Nrf2 and p62 was observed. In addition, Keap1 facilitates p62-mediated ubiquitin aggregate clearance via autophagy. A significant decrease in p62 in Nrf2 deficient APP/PS1mice may be because of increased oxidative stress in addition to the lack of Nrf2. Changes in poly-ubiquitinated proteins in APP/PS1/Nrf2-/suggests involvement of p62-Keap1-Nrf2 cascade. A further investigation is required into the pathways of beta-amyloid clearance or APP processing and behavioral changes that may have been affected by loss of Nrf2 in APP/PS1 mice.

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