TY - JOUR
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.
N1 - Publisher Copyright:
© 2017 the authors.
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.
KW - Alzheimer’s
KW - Memory
KW - Prion
KW - Transgenic
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UR - http://www.scopus.com/inward/citedby.url?scp=85029755167&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0722-17.2017
DO - 10.1523/JNEUROSCI.0722-17.2017
M3 - Article
C2 - 28842420
AN - SCOPUS:85029755167
SN - 0270-6474
VL - 37
SP - 9207
EP - 9221
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 38
ER -