The effects of peripheral hypercholesterolemia on brain cholesterol metabolism

Disrupted cholesterol homeostasis in the brain and the peripheral circulation is associated with the etiology of Alzheimer's disease (AD). Since the brain's cholesterol metabolism is segregated, attenuated cholesterol metabolism in the AD brain is unlikely to be a direct consequence of elevated plasma cholesterol. Thus, we hypothesized that there should be signals derived from the peripheral circulation secondary to the chronic hypercholesterolemia that compromises normal brain metabolism.;We induced hypercholesterolemic condition in young, middle-aged, and old male Brown Norway rats by feeding cholesterol+cholic acid supplemented purified diet (CCA) for either short-term (1 month) or long-term (3-4 month).;The CCA created a "humanized" diet-induced hypercholesterolemia (DIH) in the peripheral compartment by significantly increasing total cholesterol in plasma and liver and shifting lipoprotein peaks from HDL to VLDL, while the brain's lipid profile was solely age-dependent. ELISA on the rat brain extracts showed that pathogenic Abeta42 increased whereas neuroprotective Abeta40 decreased with advancing age, and AD pathogenic factor Abeta42/40 ratio tended to be increased by DIH. Morris water maze test revealed age-related spatial learning decline, and the age effects were somewhat accelerated by DIH. Hippocampus microarray analysis revealed that the prolonged DIH in old rats was associated with >2-fold change in expression of >2000 probe sets.;These data suggest that the development of AD-like pathologies was age-dependent and it was accelerated by DIH. The DIH effects implicate the presence of the brain-body communication which mediates peripheral changes associated with DIH to the brain, thereby aggravating AD-like pathologies.