Behavioral Disturbances without Amyloid Deposits in Mice Overexpressing Human Amyloid Precursor Protein with Flemish (A692G) or Dutch (E693Q) Mutation Samir Kumar-Singh,* ,1 Ilse Dewachter, ²,1 Dieder Moechars, ‡ Ursula Lu ¨ bke, § Chris De Jonghe,* Chantal Ceuterick, ¶ Fre ´de ´ric Checler,  Asha Naidu,** Barbara Cordell,** Patrick Cras, § Christine Van Broeckhoven,* and Fred Van Leuven ² *Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, Department of Biochemistry, § Laboratory of Neurobiology, Born-Bunge Foundation, Department of Medicine, and ¶ Laboratory of Electronmicroscopy, Born-Bunge Foundation, Department of Medicine, University of Antwerp, Antwerp, Belgium; † Experimental Genetics Group, Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology, K.U. Leuven, B3000 Louvain, Belgium; ‡ Department of Functional Genomics, Janssen Research Foundation, Beerse, Belgium;  Institut de Pharmacologie Moleculaire et Cellulaire, Valbonne, France; and **Scios, Inc., Sunnyvale, California 94086 Received April 20, 1999; revised July 10, 1999; accepted for publication September 9, 1999 The contribution of mutations in the amyloid precursor protein (APP) gene known as Flemish (APP/A692G) and Dutch (APP/E693Q) to the pathogenesis of Alzheimer’s disease and hereditary cerebral hemorrhage with amyloidosis of the Dutch type, respectively, was studied in transgenic mice that overexpress the mutant APP in brain. These transgenic mice showed the same early behavioral disturbances and defects and increased premature death as the APP/London (APP V717I), APP/ Swedish (K670N, M671L), and other APP transgenic mice described previously. Pathological changes included intense glial reaction, extensive microspongiosis in the white matter, and apoptotic neurons in select areas of the brain, while amyloid deposits were absent, even in mice over 18 months of age. This contrasts with extensive amyloid deposition in APP/London transgenic mice and less pro- nounced amyloid deposition in APP/Swedish transgenic mice generated identically. It demonstrated, however, that the behavioral deficiencies and the pathological changes in brain resulting from an impaired neuronal function are caused directly by APP or its proteolytic derivative(s). These accelerate or impinge on the normal process of aging and amyloid deposits per se are not essential for this phenotype.  2000 Academic Press Key Words: Alzheimer’s disease; transgenic mice; amyloid precursor protein; Flemish APP mutation; Dutch APP mutation. INTRODUCTION Alzheimer’s disease (AD) is a progressive neurode- generative disorder of the central nervous system and the most frequent form of dementia afflicting the aging population. The main characteristics of AD brain pathology are senile plaques and neurofibrillary tangles composed mainly of 4-kDa amyloid- peptide (A) and hyperphosphorylated microtubule-associated pro- tein , respectively, and associated with dystrophic neurites and neuronal cell loss (Price & Sisodia, 1994; Selkoe, 1994). A primary pathogenic role in AD for amyloid- precursor protein (APP) and its proteolyti- cally derived amyloid peptides (A40/42) is sug- gested by specific mutations in APP flanking the A 1 These authors contributed equally to this work. Neurobiology of Disease 7, 9–22 (2000) doi:10.1006/nbdi.1999.0272, available online at http://www.idealibrary.com on 9 0969-9961/00 $35.00 Copyright  2000 by Academic Press All rights of reproduction in any form reserved.