We have now generated homozygotes of these mice having levels of 24OH in the circulation 30-60% higher than the AbMole Clofentezine heterozygotes and about 7 fold higher than the wild types. Female homozygous CYP46A1 transgenic mice, aged 15 months, showed an improvement in spatial memory in the Morris water maze test as compared to the wild type controls. The results are discussed in relation to the hypothesis that the flux in the mevalonate pathway is of importance for memory function. Overexpression of CYP46A1 in a mouse model with increased tendency to accumulate b-amyloid in the brain was shown to decrease amyloid deposition and to improve cognition. Whether most or all of the beneficial effect of the overexpression on cognition found in that study is secondary to the reduced burden of b-amyloid or whether part of it is due to the increased flux in the mevalonate pathway is not possible to evaluate. In view of the in vitro effects of 24OH on the generation of b-amyloid, the beneficial effects demonstrated may be due to an effect of the increased levels of 24OH in the brain rather than due to the increased flux in the mevalonate pathway. The hypothesis tested here is that overexpression of CYP46A1 is also able to improve memory function in aged mice without a genetic tendency to accumulate amyloid. To this aim, we tested CYP46A1 mice and their wild type controls at an advanced age, 15 months old, in spatial and nonspatial memory tests. The homozygous CYP46A1 overexpressing mice studied here showed slightly higher levels of 24OH in the circulation, and similar increases in cholesterol precursors in the brain than the previously described heterozygotes. This was also seen in mice overexpressing CYP27 using the same promoter, where both homozygotes and heterozygotes shared similar biochemical characteristics. Our data showed that overexpression of CYP46A1 had a positive effect on spatial memory retention in MWM test. This observed enhancement of cognitive functions occurred in parallel with increased hippocampal levels of postsynaptic and presynaptic markers such as NMDAR1, p-NMDAR2A, PSD95, synapthophysin and synapsin-1. NMDA receptors, generally anchored in the postsynaptic density, are required for hippocampal synaptic plasticity as well as spatial learning and memory. Y1325 phosphorylated NMDAR2A subunit is considered a good indicator of NMDAR activity. It has been reported that loss of functional subunits, such as NMDAR1 and NMDAR2A would indicate a deficit or alteration in synaptic function. Studies in aging rodents have shown that functional impairments of these receptors are associated with spatial learning and memory deficits. Also reduction in expression and levels of presynaptic proteins, such as synapthophysin and synapsin-1, was reported in aging hippocampus and various cortical structures of human and rodents.