Lipoprotein receptor-related protein in brain and in cultured neurons of mice deficient in receptor-associated protein and transgenic for apolipoprotein E4 or amyloid precursor protein

The role of the receptor-associated protein in controlling the expression o f the low-density lipoprotein receptor-related protein was analysed in brai n and in cultured neurons of receptor-associated protein -/- mice. In addit ion, the effect of two important ligands of lipoprotein receptor-related pr otein in brain, i.e. apolipoprotein E and amyloid precursor protein, was ex amined by crossing the receptor-associated protein -/- mice with transgenic mice overexpressing these proteins specifically in neurons. The immunohist ochemical localization of lipoprotein receptor-related protein and receptor -associated protein in wildtype mouse brain was demonstrated to be congruen t over all structures, including the cortex and hippocampus. In primary hip pocampal neurons, lipoprotein receptor-related protein was distributed soma todendritically and receptor-associated protein was concentrated perinuclea rly. In hippocampal neurons from receptor-associated protein -/- mice, lipo protein receptor-related protein was redistributed over the cell body at th e expense of the dendrites. In the absence of receptor-associated protein, maturation of lipoprotein receptor-related protein is slow, resulting in ac cumulation of the uncleaved 600,000 mol. wt precursor. Neither the added ex pression of apolipoprotein E4 nor that of amyloid precursor protein in cult ured neurons influenced the maturation of lipoprotein receptor-related prot ein, in either the presence or absence of receptor-associated protein. This result shows that receptor-associated protein is not needed to allow c o-expression of lipoprotein receptor-related protein with these ligands in neurons. Furthermore, the typical ramified neuronal morphology of cultured primary neurons and the histology and architecture of the brain were normal in receptor-associated protein -/- mice and in all of the double transgeni c mice. Finally, we demonstrated that the survival of receptor-associated p rotein -/- hippocampal neurons was normal and unaffected by the genotype of the glial feeder cells, whether they were derived from wild-type mice or f rom mice deficient in receptor-associated protein or apolipoprotein E. Thes e results show that, despite the dramatic effect on maturation and cellular localization of lipoprotein receptor-related protein, the absence of recep tor-associated protein did not result in any notable physiological, functio nal or morphological effects. (C) 1999 IBRO. Published by Elsevier Science Ltd.