Conditional Deletion of <i>Prnp</i> Rescues Behavioral and Synaptic Deficits after Disease Onset in Transgenic Alzheimer's Disease

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 <i>Prnp</i> 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 catecholaminergic 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.<b>SIGNIFICANCE STATEMENT</b> The study presented here further elucidates our understanding of the soluble oligomeric amyloid-β-Aβo-binding cellular prion protein (PrP^C) signaling pathway in a familial form of Alzheimer's disease (AD) by implicating PrP^C as a potential therapeutic target for AD. In particular, genetic deletion of <i>Prnp</i> rescued several familial AD (FAD)-associated phenotypes after disease onset in a mouse model of FAD. This study underscores the therapeutic potential of PrP^C deletion given that patients already present symptoms at the time of diagnosis.