Systemic treatment with liver X receptor agonists raises apolipoprotein E, cholesterol, and amyloid-ß peptides in the cerebral spinal fluid of rats.

BACKGROUND: Apolipoprotein E (apoE) is a major cholesterol transport protein found in association with brain amyloid from Alzheimer's disease (AD) patients and the ε4 allele of apoE is a genetic risk factor for AD. Previous studies have shown that apoE forms a stable complex with amyloid ß (Aß) peptides in vitro and that the state of apoE lipidation influences the fate of brain Aß, i.e., lipid poor apoE promotes Aß aggregation/deposition while fully lipidated apoE favors Aß degradation/clearance. In the brain, apoE levels and apoE lipidation are regulated by the liver X receptors (LXRs). RESULTS: We investigated the hypothesis that increased apoE levels and lipidation induced by LXR agonists facilitates Aß efflux from the brain to the cerebral spinal fluid (CSF). We also examined if the brain expression of major apoE receptors potentially involved in apoE-mediated Aß clearance was altered by LXR agonists. ApoE, cholesterol, Aß40, and Aß42 levels were all significantly elevated in the CSF of rats after only 3 days of treatment with LXR agonists. A significant reduction in soluble brain Aß40 levels was also detected after 6 days of LXR agonist treatment. CONCLUSIONS: Our novel findings suggest that central Aß lowering caused by LXR agonists appears to involve an apoE/cholesterol-mediated transport of Aß to the CSF and that differences between the apoE isoforms in mediating this clearance pathway may explain why individuals carrying one or two copies of APOE ε4 have increased risk for AD.

Oligomers of beta-amyloid are sequestered into and seed new plaques in the brains of an AD mouse model.

Amyloid plaque deposition in the brain is a hallmark of Alzheimer's disease, but recent evidence indicates that the disease may be primarily caused by soluble amyloid-beta (1-42) (Abeta) oligomers or Abeta-derived diffusible ligands (ADDLs). ADDLs induce cognitive deficits in animal models and are thought to assemble in vitro by a mechanism apart from plaque formation. To investigate the in vivo relationship of ADDLs and plaques, biotin-labeled ADDLs (bADDLs) or amylin oligomers (bAMs) were injected into the hippocampus of hAPP overexpressing mice. The brains were collected 1 or 5 weeks after the last treatment and were processed for immunohistochemistry. Staining of tissue 1 week post-treatment showed bADDLs had diffused throughout the tissue and incorporated into plaques. Additionally, small deposits of thioflavin S-negative bADDLs were observed. At 5 weeks post-treatment, thioflavin S-positive material continued to accumulate around plaques containing bADDLs. Thioflavin S-positive material also accrued around bADDL deposits, implying that bADDLs were capable of seeding new plaques. In contrast, bAMs cleared from the brain and did not accumulate in plaques. Together, these data indicate that ADDLs are able to contribute to in vivo plaque formation in a peptide-specific manner.