[en] Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the Western world and is characterized by a progressive loss of cognitive functions leading to dementia. One major histopathological hallmark of AD is the formation of amyloid-beta plaques, which is reproduced in numerous transgenic animal models overexpressing pathogenic forms of amyloid precursor protein (APP). In human AD and in transgenic amyloid plaque mouse models, several studies report altered rates of adult neurogenesis, i.e. the formation of new neurons from neural stem and progenitor cells, and impaired neurogenesis has also been attributed to contribute to the cognitive decline in AD. So far, changes in neurogenesis have largely been considered to be a consequence of the plaque pathology. Therefore, possible alterations in neurogenesis before plaque formation or in prodromal AD have been largely ignored. Here, we analysed adult hippocampal neurogenesis in amyloidogenic mouse models of AD at different points before and during plaque progression. We found prominent alterations of hippocampal neurogenesis before plaque formation. Survival of newly generated cells and the production of new neurons were already compromised at this stage. Moreover and surprisingly, proliferation of doublecortin (DCX) expressing neuroblasts was significantly and specifically elevated during the pre-plaque stage in the APP-PS1 model, while the Nestin-expressing stem cell population was unaffected. In summary, changes in neurogenesis are evident already before plaque deposition and might contribute to well-known early hippocampal dysfunctions in prodromal AD such as hippocampal overactivity.
Disciplines :
Neurology
Author, co-author :
Unger, M S; Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria ; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
Marschallinger, J; Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria ; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
Kaindl, J; Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria ; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
Höfling, C; Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany
Rossner, S; Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany
HENEKA, Michael ; Clinical Neuroscience, Department of Neurology, University of Bonn, Bonn, Germany
Van der Linden, A; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
Aigner, Ludwig; Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria. ludwig.aigner@pmu.ac.at ; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria. ludwig.aigner@pmu.ac.at
External co-authors :
yes
Language :
English
Title :
Early Changes in Hippocampal Neurogenesis in Transgenic Mouse Models for Alzheimer's Disease.
Austrian Science Fund (AT) Austrian Science Fund Seventh Framework Programme Deutsche Forschungsgemeinschaft
Funding text :
Open access funding provided by Paracelsus Medical University. The authors thank the microscopy core facility of SCI-TReCS (Spinal Cord Injury and Tissue Regeneration Center Salzburg) and Stephanie Schwartz and Disha Shah for their support with the animal work. The authors are grateful to K. Hsiao-Ashe for providing Tg2576 mice. This work was supported by the FWF Special Research Program (SFB) F44 (F4413-B23) “Cell Signaling in Chronic CNS Disorders”, by the FWF Hertha-Firnberg Postdoctoral programme n° T736-B24, by the State Government of Salzburg, Austria, (Stiftungsprofessur, and 20204-WISS/80/199-2014), through funding from the European Union’s Seventh Framework Program (FP7/2007-2013) under grant agreements n° HEALTH-F2-2011-278850 (INMiND), n° HEALTH-F2-2011-279288 (IDEA), n° FP7-REGPOT-316120 (GlowBrain), by grants of the German Research Foundation (RO 2226/13-1) and by the German Federal Department of Education, Science and Technology (BMBF #01ED1501B) within the JPND program CrossSeeds to SR.
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