Article | Published:

Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo

Nature Communications volume 3, Article number: 1009 (2012) | Download Citation

Abstract

The amyloid beta peptide aggregates into amyloid plaques at presymptomatic stages of Alzheimer's disease, but the temporal relationship between plaque formation and neuronal dysfunction is poorly understood. Here we demonstrate that the connectivity of the peripheral olfactory neural circuit is perturbed in mice overexpressing human APPsw (Swedish mutation) before the onset of plaques. Expression of human APPsw exclusively in olfactory sensory neurons also perturbs connectivity with associated reductions in odour-evoked gene expression and olfactory acuity. By contrast, olfactory sensory neuron axons project correctly in mice overexpressing wild-type human amyloid precursor protein throughout the brain and in mice overexpressing M671V human APP, a missense mutation that reduces amyloid beta production, exclusively in olfactory sensory neurons. Furthermore, expression of Aβ40 or Aβ42 solely in the olfactory epithelium disrupts the olfactory sensory neuron axon targeting. Our data indicate that altering the structural connectivity and function of highly plastic neural circuits is one of the pleiotropic actions of soluble human amyloid beta.

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Acknowledgements

We thank R. Axel, S.D. Liberles and A.D. Albers for insightful comments; A. Nemes, M. Mendelssohn and J. Kirkland for generating the CORMAP mouse lines; L. Wu for generating the CORMAC mouse lines; C. M. William for the Arc in situ probe; H. Brown, N. Bevins, H. Wei, N. Propp, M. Glinka, M. Hood and Z. Doctor for excellent technical assistance; M. Arimon for performing the ELISA; and G. Sun for statistical analyses. This work was supported by the AFAR-Ellison Foundation (awarded to L.C.), the NIH (K08 DC04807 and DP2 OD006662, awarded to M.W.A.; P30AG036449, awarded to B.T.H.), and the Rappaport Foundation (awarded to M.W.A.).

Author information

Affiliations

  1. Department of Neurology, MassGeneral Institute of Neurodegenerative Disease, Harvard Medical School, Boston, Massachusetts 02129, USA.

    • Luxiang Cao
    • , Benjamin R. Schrank
    • , Steve Rodriguez
    • , Eric G. Benz
    • , Thomas W. Moulia
    • , Gregory T. Rickenbacher
    • , Alexis C. Gomez
    • , Sarah R. Edwards
    • , Bradley T. Hyman
    •  & Mark W. Albers
  2. Department of Neuroscience, University of Florida, Gainesville, Florida 32610, USA.

    • Yona Levites
    •  & Todd E. Golde
  3. Department of Neuroscience, Brown University, Providence, Rhode Island 02912, USA.

    • Gilad Barnea

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Contributions

L.C., S.R. and M.W.A. designed the research; L.C., B.R.S., S.R., E.G.B., T.W.M., G.T.R., A.C.G., Y.L., S.R.E. and M.W.A. performed experiments; T.E.G., B.T.H. and G.B. contributed new reagents and analytic tools; L.C., B.R.S., S.R., E.G.B., T.W.M., G.T.R. and M.W.A. analysed data; M.W.A. wrote the initial draft; all authors reviewed and revised the paper.

Competing interests

T.E.G. has received support from Myriad Genetics and Lunkbeck, Inc. T.E.G. has consulted for Elan, Lundbeck Inc., Sonexa Therapeutics and Kareus Therapeutics. B.T.H. has consulted for EMD Serrano, Janssen, Takeda, BMS, Neurophage, Pfizer, Quanterix, foldrx, Elan and Link.

Corresponding author

Correspondence to Mark W. Albers.

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DOI

https://doi.org/10.1038/ncomms2013

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