Neuronal transcriptome, tau and synapse loss in Alzheimer’s knock-in mice require prion protein

Abstract

Abstract Background Progression of Alzheimer’s disease leads to synapse loss, neural network dysfunction and cognitive failure. Accumulation of protein aggregates and brain immune activation have triggering roles in synaptic failure but the neuronal mechanisms underlying synapse loss are unclear. On the neuronal surface, cellular prion protein (PrPC) is known to be a high-affinity binding site for Amyloid-β oligomers (Aβo). However, PrPC’s dependence in knock-in AD models for tau accumulation, transcriptomic alterations and imaging biomarkers is unknown. Methods The necessity 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-seq transcriptomic profiling. Results By 9 months age, DKI mice showed learning and memory impairment, but DKI; Prnp−/− and Prnp−/− groups were indistinguishable from WT. Synapse loss in DKI brain, measured by [18F]SynVesT-1 SV2A PET or anti-SV2A immunohistology, was prevented by Prnp deletion. 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 with Prnp deletion. In contrast, astrogliosis, microgliosis and Aβ 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 by Prnp deletion associated bioinformatically with synaptic function. Additional genes were uniquely altered only in the Prnp−/− or the DKI; Prnp−/− groups. Conclusions Thus, PrPC-dependent synapse loss, phospho-tau accumulation and neuronal gene expression in AD mice can be reversed without clearing Aβ plaque or preventing gliotic reaction. This supports targeting the Aβo-PrPC interaction to prevent Aβo-neurotoxicity and pathologic tau accumulation in AD.