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/PS1E9 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 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.

SIGNIFICANCE STATEMENT 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 Prnp 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.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2xiqXoK