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

Abstract

ABSTRACTBackgroundCellular prion protein (PrPC) is a high-affinity cell-surface receptor for Amyloid-β 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 PrPCfor transcriptomic alterations driven by Aß across cell types is unexplored.MethodsThe role of PrPCwas examined as a function of age in homozygousAppNL-G-F/hMaptdouble knock-in mice (DKI). Phenotypes ofAppNL-G-F/hMaptmice with a deletion ofPrnpexpression (DKI;Prnp-/-) were compared with DKI mice with intactPrnp, mice with a targeted deletion ofPrnp (Prnp-/-), and mice with intactPrnp(WT). Phenotypes examined included behavioral deficits, synapse loss by PET imaging, synapse loss by immunohistology, tau pathology, gliosis, inflammatory markers, and snRNA-seq transcriptomic profiling.ResultsBy 9 months age, DKI mice showed learning and memory impairment, but DKI;Prnp-/-andPrnp-/-groups were indistinguishable from WT. Synapse loss in DKI brain, measured by [18F]SynVesT-1 SV2A PET or anti-SV2A immunohistology, was prevented byPrnpdeletion. Accumulation of Tau phosphorylated at aa 217 and 202/205, C1q tagging of synapses, and dystrophic neurites were all increased in DKI mice but each decreased to WT levels withPrnpdeletion. In contrast, astrogliosis, microgliosis and Aß levels were unchanged between DKI and DKI;Prnp-/-groups. Single-nuclei transcriptomics revealed differential expression in neurons and glia of DKI mice relative to WT. For DKI;Prnp-/-mice, the majority of neuronal genes differentially expressed in DKI mice were no longer significantly altered relative to WT, but most glial DKI-dependent gene expression changes persisted. The DKI-dependent neuronal genes corrected byPrnpdeletion associated bioinformatically with synaptic function. Additional genes were uniquely altered only in thePrnp-/-or the DKI;Prnp-/-groups.ConclusionsA functionalPrnpgene is required inAppNL-G-F/hMaptdouble knock-in mice for synapse loss, phospho-tau accumulation and neuronal gene expression. These data support the efficacy of targeting the Aßo-PrPCinteraction to prevent Aßo-neurotoxicity and pathologic tau accumulation in AD.