Alzheimer's Abeta, apolipoproteins and blood-brain barrier

University Of Rochester, Rochester NY

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Abstract

DESCRIPTION (provided by applicant): Amyloid [unreadable]-peptide (A[unreadable]) accumulation in brain and its neuronal toxicity contribute to the pathogenesis and progression of Alzheimer's disease (AD). A[unreadable] clearance has a key role in determining A[unreadable] 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[unreadable] clearance from brain and its retention in the CNS. We hypothesize that these interactions control (1) soluble A[unreadable] efflux across the blood-brain barrier (BBB) and from cerebrospinal fluid (CSF) and soluble A[unreadable] clearance by brain endothelial cells (BEC) and astrocytes;and (2) degradation of A[unreadable] 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[unreadable] 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[unreadable] deposition/clearance models using A[unreadable] 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[unreadable]. Aim 2 will determine apoE-assisted removal of A[unreadable] 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[unreadable]. 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[unreadable], 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[unreadable] brain accumulation, dissolve pre-existing A[unreadable] deposits and control A[unreadable]-associated cytotoxicity.