A tau-β-galactosidase (lacZ) fusion protein, followed by a neomycin (neo) resistance cassette, replaces the 3' end of exon 1 of the Cyp46a1 gene, abolishing gene function. Cyp46a1 encodes the enzyme cholesterol 24-hydroxylase which is expressed mainly in the brain, with low expression in liver. Cholesterol 24-hydroxylase is involved in cholesterol biosynthesis and turnover, and has also been implicated in the development of amyloid plaques in Alzheimer's disease. Homozygous mice are viable and fertile. In these mice, lacZ staining is evident in the spinal cord, midbrain, and hindbrain at E11.5, with expression decreasing between E11.5 and E13.5. LacZ staining is intensified between E11.5 and E13.5 in cells of the telencephalon, and the cerebral cortex. Beginning at E13.5, expression is restricted to dividing neurons in the neuroepithelium and post-mitotic neurons of the primordial plexiform layer of the telencephalon. These mice display a 40% reduction of new cholesterol synthesis in the brain, while maintaining cholesterol homeostasis in the central nervous system.
