USE OF FUSED CIRCULATIONS TO INVESTIGATE THE ROLE OF APOLIPOPROTEIN E AS AMYLOID CATALYST AND PERIPHERAL SINK IN ALZHEIMER'S DISEASE.

Apolipoprotein E (apoE) synthesized in liver and brain plays a key role in both cholesterol transport and Alzheimer's disease (AD): apoE-knockout mice develop hypercholesterolemia and atherosclerosis and cannot support AD amyloid deposition. The ApoE4 allele is the strongest genetic risk factor for late-onset AD, and apoE4 protein preferentially catalyzes amyloid-beta (Aβ) peptide fibrillization in vitro and amyloid plaque deposition in vivo. Circulating apoE may also have the potential to draw Aβ from the brain and reduce amyloid deposition. We used parabiosis to determine how circulating apoE impacts brain amyloid deposition and blood cholesterol levels in transgenic mice carrying AD-promoting APP and PS1 human transgenes-either with or without the endogenous mouse apoE gene. ApoE transferred through the joined circulations from WT to parabiosed APP+/+,PS1+/-,apoE-KO mice prevented hypercholesterolemia and reduced already low brain amyloid deposition. The findings indicate that apoE synthesis in the brain itself is necessary for amyloid accumulation. Furthermore, plasma apoE can both normalize cholesterol levels in apoE-KO mice and act as a peripheral sink to induce net efflux of Aβ peptide from the brain. The therapeutic implication is that inhibiting Alzheimer's disease neuropathology may be accomplished by either reducing apoE in the brain or increasing apoE in the blood.