Abstract 10237: Activated Protein C Protects Neurons from Alzheimer’s Disease-Related Changes Through Reduction of Tau Hyperphosphorylation

Abstract

Introduction: Activated protein C (APC) is a blood serine protease that has been shown to have neuroprotective function via its downstream signaling cascade. However, there is no study has investigated how the lack of APC signaling is associated with Alzheimer’s disease (AD)-related neuronal changes. Hypothesis: Diminished APC signaling is related to AD-associated biomarkers and behavioral symptoms. APC ameliorates these symptoms via the activation of the protein kinase B (Akt) signaling pathway which inhibits glycogen synthase kinase 3β (GSK3β) and tau hyperphosphorylation. Methods: Immunofluorescence imaging and proteomic analysis were performed on EPCR R84A/R84A mice, which had blunted APC activity due to mutated endothelial protein C receptor (EPCR), for examining amyloid β (Aβ) deposition. A rodent model of AD, 5xFAD mice, were subjected to either one-time or chronic daily APC injection (100 μg/kg/d i.p.). Morris's water maze test was performed to assess spatial memory and learning. The tissue of the hippocampus and cortex were collected for transcriptomic and proteomic analysis. Results: EPCR R84A/R84A mice showed greater hippocampal and cortical deposition of Aβ comparing to EPCR WT/WT counterparts. This result indicates defective APC signaling might contribute to the development of Aβ accumulation and insoluble plaque formation. A one-time injection of APC significantly activated AKT through phosphorylating the Ser 473 site, as well as inhibited AKT’s downstream target, GSK3β, via phosphorylation at Ser 9 in both wild-type and 5 x FAD mice. Downregulation of GSK3β activity is associated with decreased tau phosphorylation at Ser 202 /Thr 205 but not Ser 396 , indicating a reduction in the hyperphosphorylated form of tau that is prone to neurofibrillary tangle formation. Additionally, chronic APC administration for 3 months was observed to attenuate the cognitive deficits seen in 5 x FAD mice. Conclusions: APC has a crucial neuroprotective role because dampened APC signaling is related to AD-associated neuronal changes. APC has the downstream effect of Akt activation, which in turn inhibits GSK3β and the hyperphosphorylation of tau, ameliorating both the histological and behavioral markers seen in AD.