HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer’s disease

Abstract

Background: The blood-brain barrier (BBB) dysfunction represents an early feature of Alzheimer's disease (AD) that precedes the hallmarks of amyloid beta (amyloid β) plaque deposition and neuronal neurofibrillary tangle (NFT) formation. A damaged BBB correlates directly with neuroinflammation involving microglial activation and reactive astrogliosis, which is associated with increased expression and/or release of high-mobility group box protein 1 (HMGB1) and thrombin. However, the link between the presence of these molecules, BBB damage, and progression to neurodegeneration in AD is still elusive. Therefore, we aimed to profile and validate non-invasive clinical biomarkers of BBB dysfunction and neuroinflammation to assess the progression to neurodegeneration in mild cognitive impairment (MCI) and AD patients. Methods: We determined the serum levels of various proinflammatory damage-associated molecules in aged control subjects and patients with MCI or AD using validated ELISA kits. We then assessed the specific and direct effects of such molecules on BBB integrity in vitro using human primary brain microvascular endothelial cells or a cell line. Results: We observed a significant increase in serum HMGB1 and soluble receptor for advanced glycation end products (sRAGE) that correlated well with amyloid beta levels in AD patients (vs. control subjects). Interestingly, serum HMGB1 levels were significantly elevated in MCI patients compared to controls or AD patients. In addition, as a marker of BBB damage, soluble thrombomodulin (sTM) antigen, and activity were significantly (and distinctly) increased in MCI and AD patients. Direct in vitro BBB integrity assessment further revealed a significant and concentration-dependent increase in paracellular permeability to dextrans by HMGB1 or α-thrombin, possibly through disruption of zona occludins-1 bands. Pre-treatment with anti-HMGB1 monoclonal antibody blocked HMGB1 effects and leaving BBB integrity intact. Conclusions: Our current studies indicate that thrombin and HMGB1 are causal proximate proinflammatory mediators of BBB dysfunction, while sTM levels may indicate BBB endothelial damage; HMGB1 and sRAGE might serve as clinical biomarkers for progression and/or therapeutic efficacy along the AD spectrum.

Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer’s Disease

“…Advanced glycation end products and its soluble receptor have been implicated in the pathogenesis of AD [52,53]. Although not statistically significant, levels of the soluble form of RAGE (sRAGE) were decreased 48% in African Americans and indicated a medium effect size.…”

High Mobility Group Box 1 and Traumatic Brain Injury

“…Thrombin and HMGB1 are cardinal molecules of the robust host defence systems that assemble during innate immune process, coagulation, and inflammation. Barry et al proposed that they may play essential roles in the BBB disruption since both are pro-inflammatory and both are known to disrupt vascular barriers in other tissues [42].…”

Nanotherapy for Alzheimer's disease and vascular dementia: Targeting senile endothelium

“…This therapeutic approach receives added impetus from continual findings of cerebrovascular pathology (Beishon et al 2017;Goldwaser et al 2016;Hishikawa et al 2016;Kapasi and Schneider 2016;Kelleher and Soiza 2013;Malojcic et al 2017;McAleese et al 2016;Muche et al 2017;Nelson et al 2016;Nielsen et al 2017;Noh et al 2016;Perrotta et al 2016;Raz et al 2016;Weekman et al 2016) and brain arterial aging (Calabrese et al 2016;Cooper and Mitchell 2016;Gutierrez et al 2016;Kelleher and Soiza 2013;Malojcic et al 2017;Nagata et al 2016;Raz et al 2016;Toth et al 2017) accompanying Alzheimer's disease. Similarly, there is an apparent endothelium-dysfunction involvement Bhat 2015;Carradori et al 2016;Chao et al 2016;Devraj et al 2016;Di Marco et al 2015;Festoff et al 2016;Gangoda et al 2016;Hishikawa et al 2016;Hostenbach et al 2016;Kahlil et al 2016;Kelleher and Soiza 2013;Koizumi at al. 2016;Koster et al 2016;Muche et al 2017;Qosa et al 2016;Roberts et al 2016;Salmina et al 2010;Shang et al 2016; in Alzheimer's dise...…”

“…Similarly, there is an apparent endothelium-dysfunction involvement Bhat 2015;Carradori et al 2016;Chao et al 2016;Devraj et al 2016;Di Marco et al 2015;Festoff et al 2016;Gangoda et al 2016;Hishikawa et al 2016;Hostenbach et al 2016;Kahlil et al 2016;Kelleher and Soiza 2013;Koizumi at al. 2016;Koster et al 2016;Muche et al 2017;Qosa et al 2016;Roberts et al 2016;Salmina et al 2010;Shang et al 2016; in Alzheimer's disease as well as in its major risk factors (Austin et al 2015;Austin and Katusic 2016;Bogush et al 2017;Chao et al 2016;Devraj et al 2016;Festoff et al 2016;Gangoda et al 2016;Iadecola 2016;Kahlil et al 2016;Kalaria et al 2016;Kamat et al 2016;Katusic and Austin 2016;Kelleher and Soiza 2013;Khan et al 2016;Kyrtsos and Baras 2015;Perrotta et al 2016;Roberts et al 2016;Shang et al 2016;Sheen and Sheu 2016;Toda and Okamura 2016;Toth et al 2017;Uiterwijk et al 2016;Vanhoutte et al 2017;…”