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

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.