Lovastatin Differentially Affects Neuronal Cholesterol and Amyloid-β Production in vivo and in vitro.

Abstract

Epidemiological and experimental studies indicate that high cholesterol may increase susceptibility to age-associated neurodegenerative disorders, such as Alzheimer's disease (AD). Thus, it has been suggested that statins, which are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), may be a useful therapeutic tool to diminish the risk of AD. However, several studies that analyzed the therapeutic benefits of statins have yielded conflicting results. Herein, we investigated the role of lovastatin on neuronal cholesterol homeostasis and its effects on amyloid β protein production in vivo and in vitro. Lovastatin effects were analyzed in vitro using differentiated human neuroblastoma cells and in vivo in a lovastatin-fed rat model. We demonstrated that lovastatin can differentially affect the expression of APP and Aβ production in vivo and in vitro. Lovastatin-induced HMGCR inhibition was detrimental to neuronal survival in vitro via a mechanism unrelated to the reduction of cholesterol. We found that in vivo, dietary cholesterol was associated with increased Aβ production in the cerebral cortex, and lovastatin was not able to reduce cholesterol levels. However, lovastatin induced a remarkable increase in the mature form of the sterol regulatory element-binding protein-2 (SREBP-2) as well as its target gene HMGCR, in both neuronal cells and in the brain. Lovastatin modifies the mevalonate pathway without affecting cholesterol levels in vivo and is able to reduce Aβ levels only in vitro.