Conditional deletion of Prnp rescues behavioral and synaptic deficits after disease onset in transgenic Alzheimer’s disease

Santiago V. Salazar; Christopher Gallardo; Adam C. Kaufman; Charlotte S. Herber; Laura T. Haas; Sophie Robinson; Jean C. Manson; Michael K. Lee; Stephen M. Strittmatter

doi:10.1523/JNEUROSCI.0722-17.2017

Conditional deletion of Prnp rescues behavioral and synaptic deficits after disease onset in transgenic Alzheimer’s disease

Santiago V. Salazar, Christopher Gallardo, Adam C. Kaufman, Charlotte S. Herber, Laura T. Haas, Sophie Robinson, Jean C. Manson, Michael K. Lee, Stephen M. Strittmatter

Neuroscience

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

Abstract

Biochemical and genetic evidence implicate soluble oligomeric amyloid-β (Aβo) in triggering Alzheimer’s disease (AD) pathophysiology. Moreover, constitutive deletion of the Aβo-binding cellular prion protein (PrP^C) prevents development of memory deficits in APP_swe /PS1ΔE9 mice, a model of familial AD. Here, we define the role of PrP^C to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of Prnp at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for Aβo/PrP^C signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholamin-ergic neurons remains unchanged by PrP^C reduction after disease onset. These results define the potential of targeting PrP^C as a disease-modifying therapy for certain AD-related phenotypes after disease onset.

Original language	English (US)
Pages (from-to)	9207-9221
Number of pages	15
Journal	Journal of Neuroscience
Volume	37
Issue number	38
DOIs	https://doi.org/10.1523/JNEUROSCI.0722-17.2017
State	Published - Sep 20 2017

Bibliographical note

Funding Information:
Received March 16, 2017; revised July 17, 2017; accepted Aug. 11, 2017. Author contributions: S.V.S., C.G., A.C.K., L.T.H., M.K.L., and S.M.S. designed research; S.V.S., C.G., A.C.K., C.S.H., L.T.H., and S.R. performed research; J.C.M. contributed unpublished reagents/analytic tools; S.V.S., C.G., A.C.K., C.S.H., L.T.H., and S.M.S. analyzed data; S.V.S., M.K.L., and S.M.S. wrote the paper. This work was supported by the National Institutes of Health, the BrightFocus Foundation, the Alzheimer’s Association, and Falk Medical Research Trust (all to S.M.S.). We thank Stefano Sodi for assistance with mouse husbandry and Jillian Friedrich for technical assistance with sectioning the brains. S.M.S. is a cofounder of Axerion Therapeutics seeking to develop PrPC-based therapeutics for Alzheimer’s disease. The remaining authors declare no competing financial interests. Correspondence should be addressed to Stephen M. Strittmatter, CNNR Program, BCMM 436, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536. E-mail: Stephen.Strittmatter@yale.edu. DOI:10.1523/JNEUROSCI.0722-17.2017 Copyright © 2017 the authors 0270-6474/17/379207-15$15.00/0

Publisher Copyright:
© 2017 the authors.

Keywords

Alzheimer’s
Memory
Prion
Transgenic

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10.1523/JNEUROSCI.0722-17.2017

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607466

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title = "Conditional deletion of Prnp rescues behavioral and synaptic deficits after disease onset in transgenic Alzheimer{\textquoteright}s disease",

abstract = "Biochemical and genetic evidence implicate soluble oligomeric amyloid-β (Aβo) in triggering Alzheimer{\textquoteright}s disease (AD) pathophysiology. Moreover, constitutive deletion of the Aβo-binding cellular prion protein (PrPC) prevents development of memory deficits in APPswe /PS1ΔE9 mice, a model of familial AD. Here, we define the role of PrPC to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of Prnp at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for Aβo/PrPC signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholamin-ergic neurons remains unchanged by PrPC reduction after disease onset. These results define the potential of targeting PrPC as a disease-modifying therapy for certain AD-related phenotypes after disease onset.",

keywords = "Alzheimer{\textquoteright}s, Memory, Prion, Transgenic",

author = "Salazar, {Santiago V.} and Christopher Gallardo and Kaufman, {Adam C.} and Herber, {Charlotte S.} and Haas, {Laura T.} and Sophie Robinson and Manson, {Jean C.} and Lee, {Michael K.} and Strittmatter, {Stephen M.}",

note = "Funding Information: Received March 16, 2017; revised July 17, 2017; accepted Aug. 11, 2017. Author contributions: S.V.S., C.G., A.C.K., L.T.H., M.K.L., and S.M.S. designed research; S.V.S., C.G., A.C.K., C.S.H., L.T.H., and S.R. performed research; J.C.M. contributed unpublished reagents/analytic tools; S.V.S., C.G., A.C.K., C.S.H., L.T.H., and S.M.S. analyzed data; S.V.S., M.K.L., and S.M.S. wrote the paper. This work was supported by the National Institutes of Health, the BrightFocus Foundation, the Alzheimer{\textquoteright}s Association, and Falk Medical Research Trust (all to S.M.S.). We thank Stefano Sodi for assistance with mouse husbandry and Jillian Friedrich for technical assistance with sectioning the brains. S.M.S. is a cofounder of Axerion Therapeutics seeking to develop PrPC-based therapeutics for Alzheimer{\textquoteright}s disease. The remaining authors declare no competing financial interests. Correspondence should be addressed to Stephen M. Strittmatter, CNNR Program, BCMM 436, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536. E-mail: Stephen.Strittmatter@yale.edu. DOI:10.1523/JNEUROSCI.0722-17.2017 Copyright {\textcopyright} 2017 the authors 0270-6474/17/379207-15$15.00/0 Publisher Copyright: {\textcopyright} 2017 the authors.",

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T1 - Conditional deletion of Prnp rescues behavioral and synaptic deficits after disease onset in transgenic Alzheimer’s disease

AU - Salazar, Santiago V.

AU - Gallardo, Christopher

AU - Kaufman, Adam C.

AU - Herber, Charlotte S.

AU - Haas, Laura T.

AU - Robinson, Sophie

AU - Manson, Jean C.

AU - Lee, Michael K.

AU - Strittmatter, Stephen M.

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PY - 2017/9/20

Y1 - 2017/9/20

N2 - Biochemical and genetic evidence implicate soluble oligomeric amyloid-β (Aβo) in triggering Alzheimer’s disease (AD) pathophysiology. Moreover, constitutive deletion of the Aβo-binding cellular prion protein (PrPC) prevents development of memory deficits in APPswe /PS1ΔE9 mice, a model of familial AD. Here, we define the role of PrPC to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of Prnp at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for Aβo/PrPC signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholamin-ergic neurons remains unchanged by PrPC reduction after disease onset. These results define the potential of targeting PrPC as a disease-modifying therapy for certain AD-related phenotypes after disease onset.

AB - Biochemical and genetic evidence implicate soluble oligomeric amyloid-β (Aβo) in triggering Alzheimer’s disease (AD) pathophysiology. Moreover, constitutive deletion of the Aβo-binding cellular prion protein (PrPC) prevents development of memory deficits in APPswe /PS1ΔE9 mice, a model of familial AD. Here, we define the role of PrPC to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of Prnp at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for Aβo/PrPC signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholamin-ergic neurons remains unchanged by PrPC reduction after disease onset. These results define the potential of targeting PrPC as a disease-modifying therapy for certain AD-related phenotypes after disease onset.

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KW - Memory

KW - Prion

KW - Transgenic

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Conditional deletion of Prnp rescues behavioral and synaptic deficits after disease onset in transgenic Alzheimer’s disease

Abstract

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