Neuronal Transcriptome Disruption, Tau Accumulation and Synapse Loss inAlzheimer's Knock-in Mice Require Cellular Prion Protein

Cellular prion protein (PrPC) is a high-affinity cell-surface receptor for Amyloid-ß oligomers(Aßo). In certain overexpression models of Alzheimer's Disease (AD), pharmacology and genetics demonstrate its essential role for synaptic plasticity impairment, memory deficits and synapse loss. However, PrPC 's role in AD-related phenotypes with endogenous expression levels, its role in tau accumulation and its effect on imaging biomarkers are unknown. The necessity of PrPC for transcriptomic alterations driven by Aß across cell types is unexplored. Overall design: The role of PrPC was examined as a function of age in homozygous AppNL-G-F/hMapt double knock-in mice (DKI). Phenotypes of AppNL-G-F /hMapt mice with a deletion of Prnp expression (DKI; Prnp-/- ) were compared with DKI mice with intact Prnp, mice with a targeted deletion of Prnp (Prnp-/- ), and mice with intact Prnp (WT). Phenotypes examined included behavioral deficits, synapse loss by PET imaging, synapse loss by immunohistology, tau pathology, gliosis, inflammatory markers, and snRNA-seqtranscriptomic profiling.