Published online before print May 8, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.060520

Accepted for publication March 11, 2008.

Article

Neurogenesis and Alterations of Neural Stem Cells in Mouse Models of Cerebral Amyloidosis

Florian V. Ermini^*, Stefan Grathwohl^*, Rebecca Radde^*, Masohiro Yamaguchi, Matthias Staufenbiel, Theo D. Palmer^@, and Mathias Jucker^*@

Department of Cellular Neurology,* Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Department of Neurosurgery, Stanford University School of Medicine, Stanford, California; Department of Physiology Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Novartis Institutes for Biomedical Research Basel, Basel, Switzerland

^@ To whom correspondence should be addressed. E-mail: tpalmer{at}stanford.edu.

	Abstract

The hippocampus in Alzheimer's disease is burdened with amyloid plaques and is one of the few locations where neurogenesis continues throughout adult life. To evaluate the impact of amyloid-b deposition on neural stem cells, hippocampal neurogenesis was assessed using bromodeoxyuridine incorporation and doublecortin staining in two amyloid precursor protein (APP) transgenic mouse models. In 5-month-old APP23 mice prior to amyloid deposition, neurogenesis showed no robust difference relative to wild-type control mice, but 25-month-old amyloid-depositing APP23 mice showed significant increases in neurogenesis compared to controls. In contrast, 8-month-old amyloid-depositing APPPS1 mice revealed decreases in neurogenesis compared to controls. To study whether alterations in neurogenesis are the result of amyloid-induced changes at the level of neural stem cells, APPPS1 mice were crossed with mice expressing green fluorescence protein (GFP) under a central nervous system-specific nestin promoter. Eight-month-old nestin-GFP x APPPS1 mice exhibited decreases in quiescent nestin-positive astrocyte-like stem cells, while transient amplifying progenitor cells did not change in number. Strikingly, both astrocyte-like and transient-amplifying progenitor cells revealed an aberrant morphologic reaction toward congophilic amyloid-deposits. A similar reaction toward the amyloid was no longer observed in doublecortin-positive immature neurons. Results provide evidence for a disruption of neural stem cell biology in an amyloidogenic environment and support findings that neurogenesis is differently affected among various transgenic mouse models of Alzheimer's disease.