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


 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.
