The Alzheimer-related gene presenilin 1 facilitates notch 1 in primary mammalian neurons

The normal functional neurobiology of the Alzheimer's disease (AD) related gene presenilin 1 (PS1) is unknown. One clue comes from a genetic screen of Caenorhabditis elegans, which reveals that the presenilin homologue sel-12 facilitates lin-12 function [D. Levitan, I. Greenwald, Facilitation of lin -12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer' s disease gene, Nature 377 (1995) 351-355]. The mammalian homologue of lin- 12, Notch1, is a transmembrane receptor that plays an important role in cel l fate decisions during development, including neurogenesis, but does not h ave a known function in fully differentiated cells. To better understand th e potential role of Notch1 in mammalian postmitotic neurons and to test the hypothesis that Notch and PS 1 interact, we studied the effect of Notch1 t ransfection on neurite outgrowth in primary cultures of hippocampal/cortica l neurons. We demonstrate that Notch1 inhibits neurite extension, and thus has a function in postmitotic mature neurons in the mammalian CNS. Furtherm ore, we present evidence demonstrating that there is a functional interacti on between PS1 and Notch1 in mammalian neurons, analogous to the sel-12/lin -12 interaction in vulval development in C. elegans [D. Levitan, T. Doyle, D. Brousseau, M. Lee, G. Thinakaran, H. Slunt, S. Sisodia, I. Greenwald, As sessment of normal and mutant human presenilin function in Caenorhabditis e legans, Proc. Natl. Acad. Sci. U.S.A. 93 (1996) 14940-14944; D. Levitan, I. Greenwald, Effect of Sel-12 presenilin on Lin-12 localization and function in Caenorhabditis elegans, Development, 125 (1998) 3599-3606]. The inhibit ory effect of Notch1 on neurite outgrowth is markedly attenuated in neurons from PS1 knockout mice, and enhanced in neurons from transgenic mice overe xpressing wild type PS1, but not mutant PS1. These data suggest that PS1 fa cilitates Notch1 function in mammalian neurons, and support the hypothesis that a functional interaction exists between PS1 and Notch1 in postmitotic mammalian neurons. (C) 1999 Elsevier Science B.V. All rights reserved.