p75 reduces β-amyloid-induced sympathetic innervation deficits in an Alzheimer's disease mouse model
- aPeptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037; and
- bDepartment of Neurosciences, University of California at San Diego, La Jolla, CA 92093
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Communicated by Stephen F. Heinemann, The Salk Institute for Biological Studies, San Diego, CA, February 12, 2009
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↵1T.G.B. and Z.C. contributed equally to this work. (received for review December 12, 2008)
Abstract
β-Amyloid (Aβ) has adverse effects on brain cells, but little is known about its effects on the peripheral nervous system in Alzheimer's disease (AD). Several lines of in vitro evidence suggest that the neurotrophin receptor p75 mediates or exacerbates Aβ-induced neurotoxicity. Here, we show that p75-deficient sympathetic neurons are more sensitive to Aβ-induced neurite growth inhibition. To investigate the role of p75 in the sympathetic nervous system of AD, p75 mutant mice were crossed with a mouse line of AD model. The majority of p75-deficient AD mice died by 3 weeks of age. The lethality is associated with severe defects in sympathetic innervation to multiple organs. When 1 copy of the BACE1 gene encoding a protein essential in Aβ production was deleted in p75-deficient AD mice, sympathetic innervation was significantly restored. These results suggest that p75 is neuroprotective for the sympathetic nervous system in a mouse model of AD.
Footnotes
- 2To whom correspondence should be addressed. E-mail: klee{at}salk.edu
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Author contributions: T.G.B., Z.C., and D.A.O. designed research; T.G.B., Z.C., and D.A.O. performed research; E.M. contributed new reagents/analytic tools; T.G.B., Z.C., and D.A.O. analyzed data; and T.G.B., Z.C., and K.-F.L. wrote the paper.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0901533106/DCSupplemental.
