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.
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