[Abstract Title]. - Society for Neuroscience

Program#/Poster#: 244.16/M9
Topic: C.01.c. Abeta toxicity
Support: NIEHS RO1s ES10042
NIEHS RO1s ES08089
Title: The effect of Aβ(1-42) administration on Nrf2-ARE activation and differential sensitivity
of Nrf2 knockout mice in vivo
Authors: *G. JOSHI, M. VARGAS, D. JOHNSON, J. JOHNSON;
Pharm., UW-Madison, Madison, WI
Abstract: Abstract
Alzheimer‟s disease (AD) is an age associated progressive neurodegenerative disorder leading to
cognitive dysfunction and neuronal loss. It is pathologically characterized by deposition of
amyloid-beta (Aß) peptide aggregated in the form of senile plaques and hyperphosphorylated tau
as neurofibrillary tangles (NFT). Oxidative stress is known to be central to the AD pathology and
Aβ(1-42)-mediated oxidative stress has been documented. Genetic mutations in amyloid beta
precursor protein (APP), presenilin-1 and presenilin-2 are known to be involved in familial AD.
Recently researchers have shown that a transgenic mouse model expressing mutant human APP
and PS-1 had increased Aβ(1-42) production and plaque formation as well as increased
susceptibility to exogenous oxidative insult.
The antioxidant response element (ARE) is a regulatory enhancer found in 5‟ flanking region of
many phase II detoxification enzymes. Up-regulation of ARE-dependent genes has shown to be
neuroprotective. Various transcription factors and kinases are involved in ARE activation,
however NF-E2 related factor 2 (Nrf2)-mediated ARE activation is central to the induction of
phase II detoxification enzyme genes. We looked at the chronic effect of Aβ(1-42) injected intrahippocampally
in wild type and the ARE-human placental alkaline phosphatase (hPAP) reporter
mouse model. Initial studies indicate a loss of CA1 neuron and increased glial fribrillary acidic
protein (GFAP) 14 days post-injection. There was also an increase in 3-nitrotyrosine levels, a
marker of nitrosative stress, surrounding the damaged CA1 region, implicating peroxinitritemediated
oxidative stress was occurring. We observed increased ARE-hPAP activity around the
site of injection and damage indicating that the Nrf2-ARE pathway is being activated. We also
injected Aβ(1-42) into the hippocampus of Nrf2 knockout (Nrf2-/-) mice and found that
hippocampal neurons in Nrf2-/- mice were more vulnerable to Aβ(1-42)-induced toxicity.
Finally, the effect of Aβ(1-42) injection in mice overexpressing Nrf2 selectively in astrocytes
(GFAP-Nrf2 mice) is under examination. These data imply that the Nrf2-ARE pathway could
play a role in the progression of AD.
Disclosures: G. Joshi , None; M. Vargas, None; D. Johnson, None; J. Johnson, None.