Abstract

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. ? ? ?

  Funding Agency

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 #
5R37NS034467-10
Application #
7392322
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
1995-09-01
Project End
2011-03-30
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
10
Fiscal Year
2008
Total Cost
$452,031
Indirect Cost

  Institution

Name
University of Rochester
Department
Neurosurgery
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627

  Publications

Shi, Yingxiao; Lin, Shaoyu; Staats, Kim A et al. (2018) Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med 24:313-325
Montagne, Axel; Nikolakopoulou, Angeliki M; Zhao, Zhen et al. (2018) Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat Med 24:326-337
Huynh, Tien-Phat V; Liao, Fan; Francis, Caroline M et al. (2017) Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of ?-amyloidosis. Neuron 96:1013-1023.e4
Montagne, Axel; Zhao, Zhen; Zlokovic, Berislav V (2017) Alzheimer's disease: A matter of blood-brain barrier dysfunction? J Exp Med 214:3151-3169
Montagne, Axel; Nation, Daniel A; Pa, Judy et al. (2016) Brain imaging of neurovascular dysfunction in Alzheimer's disease. Acta Neuropathol 131:687-707
Barnes, Samuel R; Ng, Thomas S C; Montagne, Axel et al. (2016) Optimal acquisition and modeling parameters for accurate assessment of low Ktrans blood-brain barrier permeability using dynamic contrast-enhanced MRI. Magn Reson Med 75:1967-77
Achariyar, Thiyagaragan M; Li, Baoman; Peng, Weiguo et al. (2016) Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Mol Neurodegener 11:74
Halliday, Matthew R; Rege, Sanket V; Ma, Qingyi et al. (2016) Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab 36:216-27
Winkler, Ethan A; Nishida, Yoichiro; Sagare, Abhay P et al. (2015) GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci 18:521-530
Montagne, Axel; Barnes, Samuel R; Sweeney, Melanie D et al. (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85:296-302

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