These authors contributed equally to this work.
Mutant presenilin-1 deregulated peripheral immunity exacerbates Alzheimer-like pathology
Article first published online: 9 NOV 2009
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
Journal of Cellular and Molecular Medicine
Volume 15, Issue 2, pages 327–338, February 2011
How to Cite
Zhu, Y., Obregon, D., Hou, H., Giunta, B., Ehrhart, J., Fernandez, F., Mori, T., Nikolic, W., Zhao, Y., Morgan, D., Town, T. and Tan, J. (2011), Mutant presenilin-1 deregulated peripheral immunity exacerbates Alzheimer-like pathology. Journal of Cellular and Molecular Medicine, 15: 327–338. doi: 10.1111/j.1582-4934.2009.00962.x
- Issue published online: 9 NOV 2009
- Article first published online: 9 NOV 2009
- Accepted manuscript online: 4 AUG 2010 12:28PM EST
- Received: July 7, 2009; Accepted: October 28, 2009
- Alzheimer’s disease;
- Aβ plaques;
- bone marrow cells;
Mutations in the presenilin-1 (PS1) gene are independent causes of familial Alzheimer's disease (AD). AD patients have dysregulated immunity, and PS1 mutant mice exhibit abnormal systemic immune responses. To test whether immune function abnormality caused by a mutant human PS1 gene (mhPS1) could modify AD-like pathology, we reconstituted immune systems of AD model mice carrying a mutant human amyloid precursor protein gene (mhAPP; Tg2576 mice) or both mhAPP and mhPS1 genes (PSAPP mice) with allo-geneic bone marrow cells. Here, we report a marked reduction in amyloid-β (Aβ) levels, β-amyloid plaques and brain inflammatory responses in PSAPP mice following strain-matched wild-type PS1 bone marrow reconstitution. These effects occurred with immune switching from pro-inflammatory T helper (Th) 1 to anti-inflammatory Th2 immune responses in the periphery and in the brain, which likely instructed microglia to phagocytose and clear Aβ in an ex vivo assay. Conversely, Tg2576 mice displayed accelerated AD-like pathology when reconstituted with mhPS1 bone marrow. These data show that haematopoietic cells bearing the mhPS1 transgene exacerbate AD-like pathology, suggesting a novel therapeutic strategy for AD based on targeting PS1 in peripheral immune cells.