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.
Bibliographical noteFunding 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and S.M.S. designed research; S.V.S., C.G., A.C.K., C.S.H., L.T.H., and S.R. performed research; J.C.M. contributed unpublished reagents/analytic tools; S.V.S., C.G., A.C.K., C.S.H., L.T.H., and S.M.S. analyzed data; S.V.S., M.K.L., and S.M.S. wrote the paper.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