The cyp46a1 gene in mice causes a decrease in cholesterol synthesis by about 40%. Overexpression of this AbMole Folic acid activity would be predicted to result in an increased metabolism of cholesterol with a compensatory increase in cholesterol synthesis. In two different mouse models with overexpressed CYP46A1 the overexpression led to increased cholesterol synthesis in the brain without any changes in the levels of brain cholesterol. Based on the effects of 24OH on a- and b-secretase activity under in vitro conditions, and the assumption that increased CYP46A1 activity can be expected to decrease cholesterol content in critical membranes, we suggested that CYP46A1 activity could have a protective effect on amyloid formation in the brain. In accordance with this hypothesis, Hudry et al showed that local injection of an adenovirus associated vector encoding CYP46A1 in the cortex and hippocampus of a mouse model of the Alzheimers disease reduced amyloid deposits in the brain and improved spatial memory. In addition to the above, CYP46A1 seems to be of importance for normal memory function. A knock-out of cyp46a1 in mice resulted in severe deficiencies in spatial, associative and motor learning. These changes were associated with electrophysiological changes in hippocampal slices. Treatment of such slices of wild type mice with an inhibitor of cholesterol synthesis recapitulated the effects observed in cyp46a12/2 mice. Both the genetic and the pharmacological effects could be reversed by the addition of the non-steroid isoprenoid geranyl geraniol. It was hypothesized that a continuous formation of 24OH is a prerequisite for sufficient flux through the mevalonate pathway for the formation of adequate levels of isoprenoid products such as geranylgeraniol. The possibility was discussed that geranylation may be important for the function of some proteins that are critical for memory function. In the present work we have tested the hypothesis that an increased activity of the cholesterol 24S-hydroxylase may improve memory functions in old mice. Recently, we described a heterozygous mouse model with a stable overexpression of CYP46A1 utilizing a ubiquitous expression vector. Significant levels of human CYP46A1 protein were only found in brain, testis and eye with more than 10-fold higher levels in the brain than in the other organs. The CYP46A1 protein in the brain was located to neuronal cells. It is evident that there are very specific requirements for expression of this protein in different cells. Under normal conditions CYP46A1 protein is almost exclusively expressed in neuronal cells in the brain and in the eye. It seems likely that there a number of restrictions preventing expression of this specific protein in other cells in spite of a significant expression of the corresponding mRNA. The levels of circulating 24OH, most of which is believed to originate from the brain, were increased by a factor of 4-6 in the heterozygous mice model.