Alzheimer's disease (AD), an age associated neurodegenerative disorder, is pathologically characterized by plaques consisting of aggregated beta-amyloid (A?) and intracellular neurofibrillary tangles (NFT) formed by hyperphosphorylated tau. A? is formed by the sequential action of ? and ? secretase on the C-terminal side of amyloid precursor protein (APP). Oxidative stress has been implicated in human AD patients and several studies have shown A?-mediated oxidative stress to be central to the AD pathogenesis and progression. In addition to, or associated with oxidative stress, a reduction/dysfunction of autophagy is observed in AD. Autophagic vacuoles (AVs) that are rarely observed in neurons of healthy individuals are found to accumulate in the dystrophic and less affected neuritis in AD. Indeed, autophagy is hypothesized to be a major mechanism mediating APP turnover normally and generation of intracellular A? when dysfunctional. NF-E2- related factor 2 (Nrf2) has been implicated to be involved, not only in mitigating oxidative stress, but also an important factor in regulating and responding directly and indirectly to the changes in autophagy in vivo and in vitro. There is little work examining the role of Nrf2 in APP processing/turnover and A? production/degradation in AD with no information existing in the animal models of AD or human AD tissue. Recently, data from our laboratory found that overexpression of Nrf2 in astrocytes (GFAP-Nrf2) dramatically delays autophagic dysfunction in neurons of alpha synuclein A53T mice. This correlated with a highly significant delay in disease onset and extension of lifespan. Initial crosses of our GFAP-Nrf2 mice with APP/PS1 mice demonstrate a reduced plaque density and a dramatic reduction in intracellular APP or cleavage products. Thus, the specific aims of this proposal are:
Aim 1. To determine the effect of astrocytic Nrf2 overexpression on APP processing/turnover and A? production/degradation in APP/PS1 mice.
Aim 2. To elucidate the mechanism involved in astrocytic Nrf2-mediated changes in APP processing/turnover and A? production/degradation in astrocyte-neuron cultures derived from APP/PS1 mice.
Aim 3. To determine changes in astrocytic Nrf2 activation in possible/early and definitive/late stage human AD brain. Completion of the proposed studies will solidify the significance of astrocytic Nrf2 activation as a modulator of AD pathology.

Public Health Relevance

PROJECT 1 - PROJECT NARRATIVE These studies will help identify new ways to potentially treat AD. Completion of the aims will also provide new avenues for further investigating Nrf2 in AD through dissection the parts/proteins mediating Nrf2-dependent changes in astrocytes and secondary changes in neurons that are responsible for protecting them from developing AD pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
2P50AG033514-06
Application #
8677362
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (J1))
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
6
Fiscal Year
2014
Total Cost
$135,450
Indirect Cost
$45,450
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Melah, Kelsey E; Lu, Sharon Yuan-Fu; Hoscheidt, Siobhan M et al. (2016) Cerebrospinal Fluid Markers of Alzheimer's Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer's Disease. J Alzheimers Dis 50:873-86
Ebbert, Mark T W; Boehme, Kevin L; Wadsworth, Mark E et al. (2016) Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk. Alzheimers Dement 12:121-9
Mez, Jesse; Mukherjee, Shubhabrata; Thornton, Timothy et al. (2016) The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable. Neurobiol Aging 41:115-21
Rivera-Rivera, Leonardo A; Turski, Patrick; Johnson, Kevin M et al. (2016) 4D flow MRI for intracranial hemodynamics assessment in Alzheimer's disease. J Cereb Blood Flow Metab 36:1718-1730
Mukherjee, Jogeshwar; Bajwa, Alisha K; Wooten, Dustin W et al. (2016) Comparative assessment of (18) F-Mefway as a serotonin 5-HT1A receptor PET imaging agent across species: Rodents, nonhuman primates, and humans. J Comp Neurol 524:1457-71
Betthauser, Tobey; Lao, Patrick J; Murali, Dhanabalan et al. (2016) In vivo comparison of tau radioligands 18F-THK-5351 and 18F-THK-5317. J Nucl Med :
Gordon, Jeremy W; Niles, David J; Adamson, Erin B et al. (2016) Application of flow sensitive gradients for improved measures of metabolism using hyperpolarized (13) c MRI. Magn Reson Med 75:1242-8
Kim, Won Hwa; Hwang, Seong Jae; Adluru, Nagesh et al. (2016) Adaptive Signal Recovery on Graphs via Harmonic Analysis for Experimental Design in Neuroimaging. Comput Vis ECCV 9910:188-205
Martin, Stephen A; DeMuth, Tyler M; Miller, Karl N et al. (2016) Regional metabolic heterogeneity of the hippocampus is nonuniformly impacted by age and caloric restriction. Aging Cell 15:100-10
White, Matthew T; Shaw, Leslie M; Xie, Sharon X et al. (2016) Evaluation of Cerebrospinal Fluid Assay Variability in Alzheimer's Disease. J Alzheimers Dis 51:463-70

Showing the most recent 10 out of 211 publications