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(American Journal of Pathology. 2004;164:1495-1502.)
© 2004 American Society for Investigative Pathology

Animal Model

Hippocampal Neuron Loss Exceeds Amyloid Plaque Load in a Transgenic Mouse Model of Alzheimer’s Disease

Christoph Schmitz^*, Bart P. F. Rutten^*, Andrea Pielen, Stephanie Schäfer^¶, Oliver Wirths^¶, Günter Tremp^||, Christian Czech^||, Veronique Blanchard^||, Gerd Multhaup^**, Payam Rezaie, Hubert Korr, Harry W. M. Steinbusch^*, Laurent Pradier^|| and Thomas A. Bayer^¶

From the Department of Psychiatry and Neuropsychology,^* Division of Cellular Neuroscience, University of Maastricht, Maastricht, The Netherlands; the Department of Anatomy, Neuroembryonic Research Laboratory, University of Rostock, Rostock, Germany; the European Graduate School of Neuroscience, EURON, Maastricht, The Netherlands; the Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany; the Department of Psychiatry,^¶ Division of Neurobiology, University of Saarland Medical Center, Homburg/Saar, Germany; Aventis Pharma S.A.,|| Neurodegenerative Group and Functional Genomics, Centre de Recherche de Paris, Vitry sur Seine, France; Institut für Chemie/Biochemie,^** Freie Universität Berlin, Berlin, Germany; and the Department of Neuropathology, Institute of Psychiatry, KCL, London, United Kingdom

According to the "amyloid hypothesis of Alzheimer’s disease," ß-amyloid is the primary driving force in Alzheimer’s disease pathogenesis. Despite the development of many transgenic mouse lines developing abundant ß-amyloid-containing plaques in the brain, the actual link between amyloid plaques and neuron loss has not been clearly established, as reports on neuron loss in these models have remained controversial. We investigated transgenic mice expressing human mutant amyloid precursor protein APP751 (KM670/671NL and V717I) and human mutant presenilin-1 (PS-1 M146L). Stereologic and image analyses revealed substantial age-related neuron loss in the hippocampal pyramidal cell layer of APP/PS-1 double-transgenic mice. The loss of neurons was observed at sites of Aß aggregation and surrounding astrocytes but, most importantly, was also clearly observed in areas of the parenchyma distant from plaques. These findings point to the potential involvement of more than one mechanism in hippocampal neuron loss in this APP/PS-1 double-transgenic mouse model of Alzheimer’s disease.

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