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(American Journal of Pathology. 2005;167:161-173.)
© 2005 American Society for Investigative Pathology

Age-Related Loss of Synaptophysin Immunoreactive Presynaptic Boutons within the Hippocampus of APP751^SL, PS1^M146L, and APP751^SL/PS1^M146L Transgenic Mice

Bart P.F. Rutten^*, Nicolien M. Van der Kolk^*, Stephanie Schafer, Marc A.M.J. van Zandvoort, Thomas A. Bayer, Harry W.M. Steinbusch^* and Christoph Schmitz^*

From the Department of Psychiatry and Neuropsychology,^* Division of Cellular Neuroscience, Maastricht University, Maastricht, The Netherlands; the European Graduate School of Neuroscience, EURON, Maastricht, The Netherlands; the Department of Psychiatry, Division of Neurobiology, University of the Saarland Medical Center, Homburg/Saar, Germany; and the Department of Biophysics, Maastricht University, Maastricht, The Netherlands

Neuron and synapse loss are important features of the neuropathology of Alzheimer’s disease (AD). Recently, we observed substantial age-related hippocampal neuron loss in APP751^SL/PS1^M146L transgenic mice but not in PS1^M146L mice. Here, we investigated APP751^SL mice, PS1^M146L mice, and APP751^SL/PS1^M146L mice for age-related alterations in synaptic integrity within hippocampal stratum moleculare of the dentate gyrus (SM), stratum lucidum of area CA3 (SL), and stratum radiatum of area CA1–2 (SR) by analyzing densities and numbers of synaptophysin-immunoreactive presynaptic boutons (SIPBs). Wild-type mice, APP751^SL mice and PS1^M146L mice showed similar amounts of age-related SIPB loss within SM, and no SIPB loss within SL. Both APP751^SL mice and PS1^M146L mice showed age-related SIPB loss within SR. Importantly, APP751^SL/PS1^M146L mice displayed the severest age-related SIPB loss within SM, SL, and SR, even in regions free of extracellular Aß deposits. Together, these mouse models offer a unique framework to study the impact of several molecular and cellular events caused by mutant APP and/or mutant PS1 on age-related alterations in synaptic integrity. The observation of age-related SIPB loss within SR of PS1^M146L mice supports a role of mutant PS1 in neurodegeneration apart from its contribution to alterations in Aß generation.