Overexpression of Wild Type But Not an FAD Mutant Presenilin-1 Promotes Neurogenesis in the Hippocampus of Adult Mice Paul H. Wen,* Xiang Shao,* Zhiping Shao,* Patrick R. Hof, †,‡ Thomas Wisniewski, § Kevin Kelley, ¶ Victor L. Friedrich Jr., ‡ Lap Ho,* Giulio M. Pasinetti,* Junichi Shioi,* Nikolaos K. Robakis,* ,‡ and Gregory A. Elder* *Department of Psychiatry, the † Kastor Neurobiology of Aging Laboratories, the ‡ Fishberg Research Center for Neurobiology, and the ¶ Mouse Genetics Shared Resource Facility, Mount Sinai School of Medicine, New York, New York 10029; and § Departments of Neurology and Pathology, New York University School of Medicine, New York, New York 10016 Received August 20, 2001; revised December 11, 2001; accepted for publication March 14, 2002 Mutations in the presenilin-1 (PS-1) gene are one cause of familial Alzheimer’s disease (FAD). How- ever, the functions of the PS-1 protein as well as how PS-1 mutations cause FAD are incompletely understood. Here we investigated if neuronal overexpression of wild-type or FAD mutant PS-1 in transgenic mice affects neurogenesis in the hippocampus of adult animals. We show that either a wild-type or an FAD mutant PS-1 transgene reduces the number of neural progenitors in the dentate gyrus. However, the wild-type, but not the FAD mutant PS-1 promoted the survival and differentiation of progenitors leading to more immature granule cell neurons being generated in PS-1 wild type expressing animals. These studies suggest that PS-1 plays a role in regulating neurogenesis in adult hippocampus and that FAD mutants may have deleterious properties independent of their effects on amyloid deposition. © 2002 Elsevier Science (USA) INTRODUCTION Alzheimer’s disease (AD) is a degenerative disorder of the brain characterized clinically by progressive loss of memory along with other cognitive skills and asso- ciated with neuropathologic features including amy- loid deposits and neuronal loss. Although the etiology of AD is likely multifactorial including both genetic and environmental factors some cases show a clear pattern of autosomal dominant transmission and are referred to as familial AD (FAD). Mutations in the presenilin-1 (PS-1) gene are the most commonly rec- ognized cause of early onset FAD (St George-Hyslop, 2000). The mammalian PS-1 gene encodes an alternatively spliced mRNA (Alzheimer’s Disease Collaborative Group, 1995) that is translated into an approximately 45- to 48-kDa holoprotein. The PS-1 protein has fea- tures of a transmembrane protein (Sherrington et al., 1995) containing six to eight membrane spanning do- mains including a large cytoplasmic loop (Doan et al., 1996; Lehmann et al., 1997; Li and Greenwald, 1998; Nakai et al., 1999). However, under normal conditions nearly all of the holoprotein in most cells and tissues is cleaved into an 30-kDa N-terminal fragment (NTF) and an 18-kDa C-terminal fragment (CTF) (Thinaka- ran et al., 1996), generated by endoproteolytic cleavage within the cytoplasmic loop (Podlisny et al., 1997). Within cells PS-1 protein is located primarily in the endoplasmic reticulum and Golgi apparatus (De Strooper et al., 1997). However, the protein is found on the surface of some cells (Georgakopoulos et al., 1999) and is also transported into somatodendritic clathrin- coated vesicles (Efthimiopoulos et al., 1998) and can be found at synaptic sites (Georgakopoulos et al., 1999). Neurobiology of Disease 10, 8–19 (2002) doi:10.1006/nbdi.2002.0490 0969-9961/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved. 8