3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice

Abstract

3K3A-activated protein C (APC), a cell-signaling analogue of endogenous blood serine protease APC, exerts vasculoprotective, neuroprotective, and anti-inflammatory activities in rodent models of stroke, brain injury, and neurodegenerative disorders. 3K3A-APC is currently in development as a neuroprotectant in patients with ischemic stroke. Here, we report that 3K3A-APC inhibits BACE1 amyloidogenic pathway in a mouse model of Alzheimer’s disease (AD). We show that a 4-mo daily treatment of 3-mo-old 5XFAD mice with murine recombinant 3K3A-APC (100 µg/kg/d i.p.) prevents development of parenchymal and cerebrovascular amyloid-β (Aβ) deposits by 40–50%, which is mediated through NFκB–dependent transcriptional inhibition of BACE1, resulting in blockade of Aβ generation in neurons overexpressing human Aβ-precursor protein. Consistent with reduced Aβ deposition, 3K3A-APC normalized hippocampus-dependent behavioral deficits and cerebral blood flow responses, improved cerebrovascular integrity, and diminished neuroinflammatory responses. Our data suggest that 3K3A-APC holds potential as an effective anti-Aβ prevention therapy for early-stage AD.

Microvascular Injury in Mild Traumatic Brain Injury Accelerates Alzheimer-like Pathogenesis in Mice

“…5C). mTBI also exacerbated the BBB dysfunction in 5xFAD mice [31], as shown by >53.3% extravascular fibrin deposits in both mTBI affected cortex and hippocampus when compared with sham-operated mice at 8 DPO (Fig. 5D, E).…”

“…A hippocampus-dependent fear conditioning test was performed as previously described [31]. The experiments were performed using standard conditioning chambers housed in a soundproof isolation cubicle and equipped with a stainless-steel grid floor connected to a solid-state shock scrambler.…”

“…Aβ-positive areas were determined using ImageJ software. Briefly, the images were taken on a BZ9000 fluorescent microscope in single plain at 20× (640 × 480 µm image size) and subjected to threshold processing (Otsu) using ImageJ, and the percent area occupied by the signal in the image area was measured as described previously [31]. In each animal, four randomly selected fields from the cortex and hippocampus were imaged and analyzed in four nonadjacent sections (∼ 100 µm apart).…”

Peripheral Routes to Neurodegeneration: Passing Through the Blood–Brain Barrier

“…Some evidence supports the concept that specific dietary components may affect B-cell maturation and activity, ultimately leading to the formation of autoantibodies (Petta et al, 2018). Obesity was associated with a systemic pro-inflammatory state, characterized by changes in the frequency of B-cell Myagkova et al, 2001;Bell et al, 2010;Daneman et al, 2010;Schwartz and Shechter, 2010;Armulik et al, 2017;Kisler et al, 2017;Rustenhoven et al, 2017;Sommer et al, 2017;Montagne et al, 2018; Anti Nab Du et al, 2001;Weksler et al, 2002;Mruthinti et al, 2004;Brettschneider et al, 2005;Rosenmann et al, 2006;Gruden et al, 2007;Gustaw et al, 2008;Britschgi et al, 2009;Wilson et al, 2009;Maftei et al, 2013;Qu et al, 2014 Anti Tanaka et al, 1989;Gruden et al, 2007 (Continued) Frontiers in Aging Neuroscience | www.frontiersin.org Mecocci et al, 1995;Gruden et al, 2007;Marchi et al, 2013 Anti Kucuk et al, 2002;Kaya et al, 2003;Hong et al, Thiyagarajan et al, 2008;Zhong et al, 2009;Wang et al, 2016;Sinha et al, 2018;Lazic et al, 2019;Lyden et al, 2019 subpopulation [e.g., reduction of the anti-inflammatory IL-10 + regulatory B cell…”

“…The activated protein C (APC) therapeutic analog 3K3A-APC is a fifth option. This compound has BBB and neuro-protective properties (Thiyagarajan et al, 2008;Zhong et al, 2009;Wang et al, 2016;Sinha et al, 2018;Lazic et al, 2019;Lyden et al, 2019) and it is in clinical trial for stroke treatment (Lyden et al, 2019). Next is platelet-derived growth factor subunits BB (PDGF-BB).…”