Epidural and subdural hematomas are commonly associated with traumatic brain injury. While surgical removal is the primary intervention for these hematomas, it is also critical to prevent and reduce complications such as post-traumatic epilepsy, which may result from inflammatory responses in the injured brain areas. In the present study, we observed that high mobility group box-1 (HMGB1) decreased in the injured brain area beneath the epidural hematoma (EDH) in rats, concurrent with elevated plasma levels of HMGB1. Anti-HMGB1 monoclonal antibody therapy strongly inhibited both HMGB1 release and the subsequent increase in plasma levels. Moreover, this treatment suppressed the up-regulation of inflammatory cytokines and related molecules such as interleukin-1-beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and inducible nitric oxide synthase (iNOS) in the injured areas. Our in vitro experiments using SH-SY5Y demonstrated that hematoma components—thrombin, heme, and ferrous ion— prompted HMGB1 translocation from the nuclei to the cytoplasm, a process inhibited by the addition of the anti-HMGB1 mAb. These findings suggest that anti-HMGB1 mAb treatment not only inhibits HMGB1 translocation but also curtails inflammation in injured areas, thereby protecting the neural tissue. Thus, anti-HMGB1 mAb therapy could serve as a complementary therapy for an EDH before/after surgery.

Background: Cellular prion protein (PrP ^C ) 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, PrP ^C ’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 PrP ^C for transcriptomic alterations driven by Aß across cell types is unexplored. Methods: The role of PrP ^C was examined as a function of age in homozygous App ^NL-G-F /hMapt double knock-in mice (DKI). Phenotypes of App ^NL-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 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 by Prnp deletion associated bioinformatically with synaptic function. Additional genes were uniquely altered only in the Prnp ^-/- or the DKI; Prnp ^-/- groups. Conclusions: A functional Prnp gene is required in App ^NL-G-F /hMapt double knock-in mice for synapse loss, phospho-tau accumulation and neuronal gene expression. These data support the efficacy of targeting the Aßo-PrP ^C interaction to prevent Aßo-neurotoxicity and pathologic tau accumulation in AD.