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The Journal of Neuroscience, November 30, 2005, 25(48):11125-11132; doi:10.1523/JNEUROSCI.2545-05.2005

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Neurobiology of Disease
Invasion of Hematopoietic Cells into the Brain of Amyloid Precursor Protein Transgenic Mice

Anna K. Stalder,^1,2,3 Florian Ermini,¹ Luca Bondolfi,² Werner Krenger,³ Guido J. Burbach,⁴ Thomas Deller,⁴ Janaky Coomaraswamy,¹ Matthias Staufenbiel,⁵ Regine Landmann,³ and Mathias Jucker^1,2

¹Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany, ²Department of Neuropathology, Institute of Pathology, University of Basel, CH-4003 Basel, Switzerland, ³Department of Research, University Hospital Basel, CH-4031 Basel, Switzerland, ⁴Institute of Clinical Neuroanatomy, University of Frankfurt, D-60590 Frankfurt, Germany, and ⁵Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland

The significance of the peripheral immune system in Alzheimer's disease pathogenesis remains controversial. To study the CNS invasion of hematopoietic cells in the course of cerebral amyloidosis, we used a green fluorescence protein (GFP)-bone marrow chimeric amyloid precursor protein transgenic mouse model (APP23 mice). No difference in the number of GFP-positive invading cells was observed between young APP23 mice and nontransgenic control mice. In contrast, in aged, amyloid-depositing APP23 mice, a significant increase in the number of invading ameboid-like GFP-positive cells was found compared with age-matched nontransgenic control mice. Interestingly, independent of the time after transplantation, only a subpopulation of amyloid deposits was surrounded by invading cells. This suggests that not all amyloid plaques are a target for invading cells or, alternatively, all amyloid plaques attract invading cells but only for a limited time, possibly at an early stage of plaque evolution. Immunological and ultrastructural phenotyping revealed that macrophages and T-cells accounted for a significant portion of these ameboid-like invading cells. Macrophages did not show evidence of amyloid phagocytosis at the electron microscopic level, and no obvious signs for T-cell-mediated inflammation or neurodegeneration were observed. The observation that hematopoietic cells invade the brain in response to cerebral amyloidosis may hold an unrecognized therapeutic potential.

Key words: Alzheimer; glia; microglia; amyloid; neuroinflammation; GFP; macrophages; transgenic mouse; aging; bone marrow chimera

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Received June 21, 2005; revised September 15, 2005; accepted October 9, 2005.

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