Lindsay Poppe1,2, Laura Rué1,2, Mieke Timmers1,2, Annette Lenaerts1,2, Annet Storm1,2, Zsuzsanna Callaerts-Vegh3,4, Gilles Courtand5, Antina de Boer1,2, Silke Smolders1,2, Philip Van Damme1,2,6, Ludo Van Den Bosch1,2, Rudi D'Hooge3, Bart De Strooper7,8,9, Wim Robberecht1,6, Robin Lemmens10,11,12. 1. Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute (LBI), KU Leuven - University of Leuven, Leuven, Belgium. 2. Laboratory of Neurobiology, Center for Brain and Disease Research, VIB, Leuven, Belgium. 3. Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, KU Leuven - University of Leuven, Leuven, Belgium. 4. mINT Animal Behavior Core Facility, Faculty of Psychology, KU Leuven, Leuven, Belgium. 5. Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Unité Mixte de Recherche 5287, Centre National de la Recherche Scientifique, Université de Bordeaux, 33076, Bordeaux, France. 6. Department of Neurology, University Hospitals Leuven, Herestraat 49, B-3000, Leuven, Belgium. 7. VIB Center for Brain and Disease Research, Leuven, Belgium. 8. Department of Neurosciences, Katholieke Universiteit Leuven, Leuven, Belgium. 9. UK Dementia Research Institute at University College London, London, UK. 10. Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute (LBI), KU Leuven - University of Leuven, Leuven, Belgium. robin.lemmens@uzleuven.be. 11. Laboratory of Neurobiology, Center for Brain and Disease Research, VIB, Leuven, Belgium. robin.lemmens@uzleuven.be. 12. Department of Neurology, University Hospitals Leuven, Herestraat 49, B-3000, Leuven, Belgium. robin.lemmens@uzleuven.be.
Abstract
BACKGROUND: EphA4 is a receptor of the ephrin system regulating spine morphology and plasticity in the brain. These processes are pivotal in the pathophysiology of Alzheimer's disease (AD), characterized by synapse dysfunction and loss, and the progressive loss of memory and other cognitive functions. Reduced EphA4 signaling has been shown to rescue beta-amyloid-induced dendritic spine loss and long-term potentiation (LTP) deficits in cultured hippocampal slices and primary hippocampal cultures. In this study, we investigated whether EphA4 ablation might preserve synapse function and ameliorate cognitive performance in the APPPS1 transgenic mouse model of AD. METHODS: A postnatal genetic ablation of EphA4 in the forebrain was established in the APPPS1 mouse model of AD, followed by a battery of cognitive tests at 9 months of age to investigate cognitive function upon EphA4 loss. A Golgi-Cox staining was used to explore alterations in dendritic spine density and morphology in the CA1 region of the hippocampus. RESULTS: Upon EphA4 loss in APPPS1 mice, we observed improved social memory in the preference for social novelty test without affecting other cognitive functions. Dendritic spine analysis revealed altered synapse morphology as characterized by increased dendritic spine length and head width. These modifications were independent of hippocampal plaque load and beta-amyloid peptide levels since these were similar in mice with normal versus reduced levels of EphA4. CONCLUSION: Loss of EphA4 improved social memory in a mouse model of Alzheimer's disease in association with alterations in spine morphology.
BACKGROUND:EphA4 is a receptor of the ephrin system regulating spine morphology and plasticity in the brain. These processes are pivotal in the pathophysiology of Alzheimer's disease (AD), characterized by synapse dysfunction and loss, and the progressive loss of memory and other cognitive functions. Reduced EphA4 signaling has been shown to rescue beta-amyloid-induced dendritic spine loss and long-term potentiation (LTP) deficits in cultured hippocampal slices and primary hippocampal cultures. In this study, we investigated whether EphA4 ablation might preserve synapse function and ameliorate cognitive performance in the APPPS1 transgenicmouse model of AD. METHODS: A postnatal genetic ablation of EphA4 in the forebrain was established in the APPPS1 mouse model of AD, followed by a battery of cognitive tests at 9 months of age to investigate cognitive function upon EphA4 loss. A Golgi-Cox staining was used to explore alterations in dendritic spine density and morphology in the CA1 region of the hippocampus. RESULTS: Upon EphA4 loss in APPPS1 mice, we observed improved social memory in the preference for social novelty test without affecting other cognitive functions. Dendritic spine analysis revealed altered synapse morphology as characterized by increased dendritic spine length and head width. These modifications were independent of hippocampal plaque load and beta-amyloid peptide levels since these were similar in mice with normal versus reduced levels of EphA4. CONCLUSION: Loss of EphA4 improved social memory in a mouse model of Alzheimer's disease in association with alterations in spine morphology.
Authors: Courtney K Walker; Kelsey M Greathouse; Evan Liu; Hamad M Muhammad; Benjamin D Boros; Cameron D Freeman; Jung Vin Seo; Jeremy H Herskowitz Journal: Neuroscience Date: 2022-06-23 Impact factor: 3.708
Authors: Ryan J Bevan; Tim R Hughes; Pete A Williams; Mark A Good; B Paul Morgan; James E Morgan Journal: Acta Neuropathol Commun Date: 2020-12-07 Impact factor: 7.801