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-beta (Aβo) in triggering Alzheimer9s 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 pre-existing 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 was 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 Aβo-PrP C signaling pathway in a familial form of Alzheimer9s 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.