The neurovascular hypothesis states that an impaired brain-to-blood efflux of amyloid ? protein (ABP) at the vascular blood-brain barrier (BBB) is an important mechanism underlying ABP accumulation and cognitive impairments in patients with Alzheimer's disease (AD). Low-density lipoprotein receptor-related protein-1 (LRP) has been identified as the major efflux pump at the BBB for ABP. Zlokovic and co-workers have shown that LRP is deficient in the BBB of patients with AD and of Hsiao mice that overexpress amyloid precursor peptide (APP). We have shown that ABP efflux is impaired at the BBB in animals which overexpress ABP and that knockdown of APP expression with antisense restores BBB efflux of ABP. This suggests that ABP poisons its own transporter, LRP. Our goal is to determine whether the mechanism of impaired efflux of ABP is caused by ABP-induced oxidative damage to LRP. ABP, especially in its oligomeric form, induces oxidative stress and by this mechanism impairs the function of transporters other than LRP in non-BBB tissues. LRP in non-BBB tissues is already known to be readily oxidized and its ability to transport its other ligands in those tissues is impaired in its oxidative state. Our hypothesis is that ABP impairs its own efflux at the BBB by oxidizing LRP. We will test this hypothesis in 3 Specific Aims:
Specific Aim 1 : To determine in vivo whether mice that do overexpress APP have an oxidized LRP and whether ABP efflux can be restored to normal rates by treatments which reduce ABP or by antioxidants.
Specific Aim 2 : To determine the role of ABP and oxidation in impairing BBB efflux of ABP in vitro in a BBB monolayer model that uses brain endothelial cells derived from mice that do not overexpress APP.
Specific Aim 3 : To determine the status of oxidative modification of LRP in human brain tissue obtained at short post mortem intervals (PMI;specifically, <4h after death) from patients with AD and mild cognitive impairment (MCI) relative to that from control brain tissue and correlate this information to the level and oligomeric status of ABP1-42 in those same brains and to compare this to a similar analysis for the mice that overepress APP.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG029839-05
Application #
8239926
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Petanceska, Suzana
Project Start
2008-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$273,237
Indirect Cost
$41,479
Name
Seattle Institute for Biomedical/Clinical Research
Department
Type
DUNS #
928470061
City
Seattle
State
WA
Country
United States
Zip Code
98108
Banks, William A; Dohi, Kenji; Hansen, Kim et al. (2016) Assessing blood granulocyte colony-stimulating factor as a potential biomarker of acute traumatic brain injury in mice and humans. Brain Behav Immun 52:81-7
Urayama, Akihiko; Grubb, Jeffrey H; Sly, William S et al. (2016) Pharmacologic manipulation of lysosomal enzyme transport across the blood-brain barrier. J Cereb Blood Flow Metab 36:476-86
Banks, W A (2015) The blood-brain barrier in neuroimmunology: Tales of separation and assimilation. Brain Behav Immun 44:1-8
Banks, William A; Gray, Alicia M; Erickson, Michelle A et al. (2015) Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit. J Neuroinflammation 12:223
Hong, Suzi; Banks, William A (2015) Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications. Brain Behav Immun 45:1-12
Armbrecht, Harvey J; Siddiqui, Akbar M; Green, Michael et al. (2015) Antisense against Amyloid-β Protein Precursor Reverses Memory Deficits and Alters Gene Expression in Neurotropic and Insulin-Signaling Pathways in SAMP8 Mice. J Alzheimers Dis 46:535-48
Erickson, Michelle A; Morofuji, Yoichi; Owen, Joshua B et al. (2014) Rapid transport of CCL11 across the blood-brain barrier: regional variation and importance of blood cells. J Pharmacol Exp Ther 349:497-507
Farr, Susan A; Erickson, Michelle A; Niehoff, Michael L et al. (2014) Central and peripheral administration of antisense oligonucleotide targeting amyloid-β protein precursor improves learning and memory and reduces neuroinflammatory cytokines in Tg2576 (AβPPswe) mice. J Alzheimers Dis 40:1005-16
Dohi, Kenji; Kraemer, Brian C; Erickson, Michelle A et al. (2014) Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury. PLoS One 9:e108034
Salameh, Therese S; Banks, William A (2014) Delivery of therapeutic peptides and proteins to the CNS. Adv Pharmacol 71:277-99

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