Amyloid ?-peptide (A?) accumulation in brain and its neuronal toxicity contribute to the pathogenesis and progression of Alzheimer's disease (AD). A? clearance has a key role in determining A? concentration in the CNS. We hypothesize that the interactions between apolipoprotein (apo) E and the low density lipoprotein receptor (LDLR) and the interactions between apoJ and LDLR-related protein 2 (LRP2) regulate A? clearance from brain and its retention in the CNS. We hypothesize that these interactions control (1) soluble A? efflux across the blood-brain barrier (BBB) and from cerebrospinal fluid (CSF) and soluble A? clearance by brain endothelial cells (BEC) and astrocytes;and (2) degradation of A? deposits by BEC and astrocytes. The research design proposes to test these hypotheses (1) in an in vivo murine clearance model using exogenous human unlabeled A(3/apolipoproteins in wild type and LDLR-/- mice and in mice with blockade of LRP2 pathway;(2) in an in vivo model of endogenous soluble A? clearance using microdialysis in APPsw mice, APPsw/apoE-/- mice, APPsw mice expressing apoE2, apoES and apoE4, and APPsw/apoJ-/- mice;and (3) in in vitro A? deposition/clearance models using A? coated surfaces and brain tissue sections from APPsw transgenic mice. Using these deposition/clearance models, we will access BEC and astrocytes that are wild type, express apoES or apoE4, or lack expression of apoJ, apoE, both apoE and apoJ, and LDLR.
Aim 1 will determine effects of apoE on retention, BBB and CSF-to-blood efflux and cellular clearance of soluble A?.
Aim 2 will determine apoE-assisted removal of A? deposits in vitro and from APPsw mice.
Aim 3 will determine effects of apoJ on BBB and CSF-to-blood efflux and cellular clearance of soluble A?.
Aim 4 will determine effects of apoJ on A? removal in vitro and from APPsw mice. Since apoE, apoJ and the LDLR and LRP2 are potential drug targets for lowering brain A?, understanding their functions in vivo in different animal models and in vitro on BEC and astrocytes may help developing strategies to prevent and/or decelerate A? brain accumulation, dissolve pre-existing A? deposits and control A?-associated cytotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS034467-15
Application #
8457024
Study Section
Special Emphasis Panel (NSS)
Program Officer
Corriveau, Roderick A
Project Start
1995-09-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
15
Fiscal Year
2013
Total Cost
$491,755
Indirect Cost
$145,915
Name
University of Southern California
Department
Physiology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Winkler, Ethan A; Sengillo, Jesse D; Sagare, Abhay P et al. (2014) Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc Natl Acad Sci U S A 111:E1035-42
Zhao, Zhen; Zlokovic, Berislav V (2014) Blood-brain barrier: a dual life of MFSD2A? Neuron 82:728-30
Sagare, Abhay P; Bell, Robert D; Zlokovic, Berislav V (2013) Neurovascular defects and faulty amyloid-* vascular clearance in Alzheimer's disease. J Alzheimers Dis 33 Suppl 1:S87-100
Sagare, Abhay P; Bell, Robert D; Srivastava, Alaka et al. (2013) A lipoprotein receptor cluster IV mutant preferentially binds amyloid-* and regulates its clearance from the mouse brain. J Biol Chem 288:15154-66
Zlokovic, Berislav V (2013) Cerebrovascular effects of apolipoprotein E: implications for Alzheimer disease. JAMA Neurol 70:440-4
Sengillo, Jesse D; Winkler, Ethan A; Walker, Corey T et al. (2013) Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease. Brain Pathol 23:303-10
Halliday, Matthew R; Pomara, Nunzio; Sagare, Abhay P et al. (2013) Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood-brain barrier breakdown. JAMA Neurol 70:1198-200
Castellano, Joseph M; Kim, Jungsu; Stewart, Floy R et al. (2011) Human apoE isoforms differentially regulate brain amyloid-? peptide clearance. Sci Transl Med 3:89ra57
Zlokovic, Berislav V (2011) Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 12:723-38
Sagare, Abhay P; Deane, Rashid; Zetterberg, Henrik et al. (2011) Impaired lipoprotein receptor-mediated peripheral binding of plasma amyloid-* is an early biomarker for mild cognitive impairment preceding Alzheimer's disease. J Alzheimers Dis 24:25-34

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