Publications by authors named "Cheryl L Wellington"

80 Publications

Characterization of CSF ubiquitin C-terminal hydrolase L1 (UCH-L1) as a biomarker of human acute traumatic spinal cord injury.

J Neurotrauma 2021 Jan 27. Epub 2021 Jan 27.

Univ. of British Columbia, Orthopaedics, 6169 Blusson Spinal Cord Centre, 818 West 10th Ave, Vancouver, British Columbia, Canada, V5Z1M9;

A major obstacle for translational research in acute spinal cord injury (SCI) is the lack of biomarkers that can objectively stratify injury severity and predict outcome. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that shows promise as a diagnostic biomarker in traumatic brain injury (TBI), but has not been studied in SCI. In this study, cerebrospinal fluid (CSF) and serum samples were collected over the first 72-96 hours post-injury from 32 acute SCI patients who were followed prospectively to determine neurologic outcomes at 6 months post-injury. UCH-L1 concentration was measured using the Quanterix Simoa platform and correlated to injury severity, time, and neurologic recovery. We found that CSF UCH-L1 was significantly elevated by 10-100-fold over laminectomy controls in an injury severity and time dependent manner. 24h post-injury CSF UCH-L1 concentrations distinguished between AIS A and AIS B, and AIS A and AIS C patients in the acute setting, and predicted who would remain "motor complete" (AIS A/B) at 6-months with a sensitivity of 100% and a specificity of 86%. AIS A subjects who did not improve their AIS grade at 6-months post-injury were characterized by sustained elevations in CSF UCH-L1 up to 96 hours. Similarly, the failure to gain more than 8 points on the total motor score at 6 months post-injury was associated with higher 24h CSF UCH-L1. Unfortunately, serum UCH-L1 levels were not informative about injury severity or outcome. In conclusion, CSF UCH-L1 in acute SCI shows promise as a biomarker to reflect injury severity and to predict outcome. Keywords: UCH-L1; biomarker; spinal cord injury; cerebrospinal fluid; prognosis.
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http://dx.doi.org/10.1089/neu.2020.7352DOI Listing
January 2021

Assessing the importance of interleukin-6 in COVID-19.

Lancet Respir Med 2021 02 15;9(2):e13. Epub 2021 Jan 15.

Division of Critical Care Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, V5Z1M9, Canada.

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http://dx.doi.org/10.1016/S2213-2600(20)30600-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836242PMC
February 2021

An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases.

Mol Neurodegener 2020 11 19;15(1):70. Epub 2020 Nov 19.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.

Introduction: The neurovascular unit (NVU) - the interaction between the neurons and the cerebrovasculature - is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently no in vitro 3-dimensional (3D) perfusible model of the human cortical arterial NVU.

Method: We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries.

Results: This system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It reproduces key characteristics of cortical neurons and astrocytes and enables formation of a selective and functional endothelial barrier. We provide proof-of-principle data showing that this in vitro human arterial NVU may be suitable to study neurovascular components of neurodegenerative diseases such as Alzheimer's disease (AD), as endogenously produced phosphorylated tau and beta-amyloid accumulate in the model over time. Finally, neuronal and glial fluid biomarkers relevant to neurodegenerative diseases are measurable in our arterial NVU model.

Conclusion: This model is a suitable research tool to investigate arterial NVU functions in healthy and disease states. Further, the design of the platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.
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http://dx.doi.org/10.1186/s13024-020-00418-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678181PMC
November 2020

The Association of Inflammatory Cytokines in the Pulmonary Pathophysiology of Respiratory Failure in Critically Ill Patients With Coronavirus Disease 2019.

Crit Care Explor 2020 Sep 17;2(9):e0203. Epub 2020 Sep 17.

Division of Critical Care Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.

Objectives: The majority of coronavirus disease 2019 mortality and morbidity is attributable to respiratory failure from severe acute respiratory syndrome coronavirus 2 infection. The pathogenesis underpinning coronavirus disease 2019-induced respiratory failure may be attributable to a dysregulated host immune response. Our objective was to investigate the pathophysiological relationship between proinflammatory cytokines and respiratory failure in severe coronavirus disease 2019.

Design: Multicenter prospective observational study.

Setting: ICU.

Patients: Critically ill patients with coronavirus disease 2019 and noncoronavirus disease 2019 critically ill patients with respiratory failure (ICU control group).

Interventions: Daily measurement of serum inflammatory cytokines.

Measurements And Main Results: Demographics, comorbidities, clinical, physiologic, and laboratory data were collected daily. Daily serum samples were drawn for measurements of interleukin-1β, interleukin-6, interleukin-10, and tumor necrosis factor-α. Pulmonary outcomes were the ratio of Pao/Fio and static lung compliance. Twenty-six patients with coronavirus disease 2019 and 22 ICU controls were enrolled. Of the patients with coronavirus disease 2019, 58% developed acute respiratory distress syndrome, 62% required mechanical ventilation, 12% underwent extracorporeal membrane oxygenation, and 23% died. A negative correlation between interleukin-6 and Pao/Fio (rho, -0.531; = 0.0052) and static lung compliance (rho, -0.579; = 0.033) was found selectively in the coronavirus disease 2019 group. Diagnosis of acute respiratory distress syndrome was associated with significantly elevated serum interleukin-6 and interleukin-1β on the day of diagnosis.

Conclusions: The inverse relationship between serum interleukin-6 and Pao/Fio and static lung compliance is specific to severe acute respiratory syndrome coronavirus 2 infection in critically ill patients with respiratory failure. Similar observations were not found with interleukin-β or tumor necrosis factor-α.
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http://dx.doi.org/10.1097/CCE.0000000000000203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515615PMC
September 2020

Quantification of Neurological Blood-Based Biomarkers in Critically Ill Patients With Coronavirus Disease 2019.

Crit Care Explor 2020 Oct 2;2(10):e0238. Epub 2020 Oct 2.

Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.

Objectives: To provide an objective characterization of acute neurologic injury in critically ill patients with coronavirus disease 2019.

Design: Prospective observational study. Demographics, comorbidities, and daily clinical physiologic and laboratory data were collected. Plasma levels of neurofilament-light chain, total tau, ubiquitin carboxy-terminal hydrolase L1, and glial fibrillary acidic protein were measured. The primary neurologic outcome was delirium defined by the Intensive Care Delirium Screening Checklist (scale 1-8). Associations among plasma biomarkers, respiratory failure, and inflammation were analyzed.

Setting: Multicenter study in ICUs.

Patients: Critically ill patients with respiratory failure, with coronavirus disease 2019, or without (ICU control).

Measurements And Main Results: A total of 27 patients with coronavirus disease 2019 and 19 ICU controls were enrolled. Compared with ICU controls with pneumonia of other etiology, patients with coronavirus disease 2019 had significantly higher glial fibrillary acidic protein (272 pg/mL [150-555 pg/mL] vs 118 pg/mL [78.5-168 pg/mL]; = 0.0009). In coronavirus disease 2019 patients, glial fibrillary acidic protein (rho = 0.5115, = 0.0064), ubiquitin carboxy-terminal hydrolase L1 (rho = 0.4056, = 0.0358), and neurofilament-light chain (rho = 0.6223, = 0.0005) positively correlated with Intensive Care Delirium Screening Checklist score and were increased in patients with delirium (Intensive Care Delirium Screening Checklist ≥ 4) in the coronavirus disease 2019 group but not in ICU controls. There were no associations between the measures of respiratory function or cytokines with glial fibrillary acidic protein, total tau, ubiquitin carboxy-terminal hydrolase L1, or neurofilament-light chain levels in patients with coronavirus disease 2019.

Conclusions: Plasma glial fibrillary acidic protein is two-fold higher in critically ill patients with coronavirus disease 2019 compared with ICU controls. Higher levels of glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, and neurofilament-light chain associate with delirium in patients with coronavirus disease 2019. Elevated plasma glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, and neurofilament-light chain are independent of respiratory function and peripheral cytokines.
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http://dx.doi.org/10.1097/CCE.0000000000000238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535554PMC
October 2020

The association of ABO blood group with indices of disease severity and multiorgan dysfunction in COVID-19.

Blood Adv 2020 10;4(20):4981-4989

Division of Critical Care Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.

Studies on severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) suggest a protective effect of anti-A antibodies against viral cell entry that may hold relevance for SARS-CoV-2 infection. Therefore, we aimed to determine whether ABO blood groups are associated with different severities of COVID-19. We conducted a multicenter retrospective analysis and nested prospective observational substudy of critically ill patients with COVID-19. We collected data pertaining to age, sex, comorbidities, dates of symptom onset, hospital admission, intensive care unit (ICU) admission, mechanical ventilation, continuous renal replacement therapy (CRRT), standard laboratory parameters, and serum inflammatory cytokines. National (N = 398 671; P = .38) and provincial (n = 62 246; P = .60) ABO blood group distributions did not differ from our cohort (n = 95). A higher proportion of COVID-19 patients with blood group A or AB required mechanical ventilation (P = .02) and CRRT (P = .004) and had a longer ICU stay (P = .03) compared with patients with blood group O or B. Blood group A or AB also had an increased probability of requiring mechanical ventilation and CRRT after adjusting for age, sex, and presence of ≥1 comorbidity. Inflammatory cytokines did not differ between patients with blood group A or AB (n = 11) vs O or B (n = 14; P > .10 for all cytokines). Collectively, our data indicate that critically ill COVID-19 patients with blood group A or AB are at increased risk for requiring mechanical ventilation, CRRT, and prolonged ICU admission compared with patients with blood group O or B. Further work is needed to understand the underlying mechanisms.
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http://dx.doi.org/10.1182/bloodadvances.2020002623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594392PMC
October 2020

Vascular contributions to cognitive impairment and dementia (VCID): A report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop.

Alzheimers Dement 2020 12 8;16(12):1714-1733. Epub 2020 Oct 8.

National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

Vascular contributions to cognitive impairment and dementia (VCID) are characterized by the aging neurovascular unit being confronted with and failing to cope with biological insults due to systemic and cerebral vascular disease, proteinopathy including Alzheimer's biology, metabolic disease, or immune response, resulting in cognitive decline. This report summarizes the discussion and recommendations from a working group convened by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke to evaluate the state of the field in VCID research, identify research priorities, and foster collaborations. As discussed in this report, advances in understanding the biological mechanisms of VCID across the wide spectrum of pathologies, chronic systemic comorbidities, and other risk factors may lead to potential prevention and new treatment strategies to decrease the burden of dementia. Better understanding of the social determinants of health that affect risks for both vascular disease and VCID could provide insight into strategies to reduce racial and ethnic disparities in VCID.
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http://dx.doi.org/10.1002/alz.12157DOI Listing
December 2020

Confronting the controversy: interleukin-6 and the COVID-19 cytokine storm syndrome.

Eur Respir J 2020 10 1;56(4). Epub 2020 Oct 1.

Division of Critical Care Medicine, Dept of Medicine, University of British Columbia, Vancouver, BC, Canada.

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http://dx.doi.org/10.1183/13993003.03006-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474149PMC
October 2020

Alternatives to amyloid for Alzheimer's disease therapies-a symposium report.

Ann N Y Acad Sci 2020 09 29;1475(1):3-14. Epub 2020 May 29.

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

For decades, Alzheimer's disease research has focused on amyloid as the primary pathogenic agent. This focus has driven the development of numerous amyloid-targeting therapies; however, with one possible exception, none of these therapies have been effective in preventing or delaying cognitive decline in patients, and there are no approved disease-modifying agents. It is becoming more apparent that alternative drug targets are needed to address this complex disease. An increased understanding of Alzheimer's disease pathology has highlighted the need to target the appropriate disease pathology at the appropriate time in the disease course. Preclinical and early clinical studies have focused on targets, including inflammation, tau, vascular health, and the microbiome. This report summarizes the presentations from a New York Academy of Sciences' one-day symposium entitled "Alzheimer's Disease Therapeutics: Alternatives to Amyloid," held on November 20, 2019.
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http://dx.doi.org/10.1111/nyas.14371DOI Listing
September 2020

Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes.

Blood Rev 2021 01 15;45:100707. Epub 2020 May 15.

Division of Hematology, University of British Columbia, Canada.

A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.
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http://dx.doi.org/10.1016/j.blre.2020.100707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227559PMC
January 2021

Axl receptor tyrosine kinase is a regulator of apolipoprotein E.

Mol Brain 2020 05 4;13(1):66. Epub 2020 May 4.

Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada.

Alzheimer's disease (AD), the leading cause of dementia, is a chronic neurodegenerative disease. Apolipoprotein E (apoE), which carries lipids in the brain in the form of lipoproteins, plays an undisputed role in AD pathophysiology. A high-throughput phenotypic screen was conducted using a CCF-STTG1 human astrocytoma cell line to identify small molecules that could upregulate apoE secretion. AZ7235, a previously discovered Axl kinase inhibitor, was identified to have robust apoE activity in brain microglia, astrocytes and pericytes. AZ7235 also increased expression of ATP-binding cassette protein A1 (ABCA1), which is involved in the lipidation and secretion of apoE. Moreover, AZ7235 did not exhibit Liver-X-Receptor (LXR) activity and stimulated apoE and ABCA1 expression in the absence of LXR. Target validation studies using AXL-/- CCF-STTG1 cells showed that Axl is required to mediate AZ7235 upregulation of apoE and ABCA1. Intriguingly, apoE expression and secretion was significantly attenuated in AXL-deficient CCF-STTG1 cells and reconstitution of Axl or kinase-dead Axl significantly restored apoE baseline levels, demonstrating that Axl also plays a role in maintaining apoE homeostasis in astrocytes independent of its kinase activity. Lastly, these effects may require human apoE regulatory sequences, as AZ7235 exhibited little stimulatory activity toward apoE and ABCA1 in primary murine glia derived from neonatal human APOE3 targeted-replacement mice. Collectively, we identified a small molecule that exhibits robust apoE and ABCA1 activity independent of the LXR pathway in human cells and elucidated a novel relationship between Axl and apoE homeostasis in human astrocytes.
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http://dx.doi.org/10.1186/s13041-020-00609-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197143PMC
May 2020

Cerebrovascular amyloid Angiopathy in bioengineered vessels is reduced by high-density lipoprotein particles enriched in Apolipoprotein E.

Mol Neurodegener 2020 03 25;15(1):23. Epub 2020 Mar 25.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.

Background: Several lines of evidence suggest that high-density lipoprotein (HDL) reduces Alzheimer's disease (AD) risk by decreasing vascular beta-amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood.

Methods: Here we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding.

Results: We demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. We describe multiple novel mechanisms by which HDL acts to reduce CAA, namely: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) lowering collagen-I protein levels produced by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake into SMC that associates with reduced low density lipoprotein related protein 1 (LRP1) levels. Furthermore, we show that HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects, providing new insights into the peripheral role of apoE in AD, in particular, the fraction of HDL that contains apoE.

Conclusion: The findings in this study identify new mechanisms by which circulating HDL, particularly HDL particles enriched in apoE, may provide vascular resilience to Aβ and shed new light on a potential role of peripherally-acting apoE in AD.
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http://dx.doi.org/10.1186/s13024-020-00366-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093966PMC
March 2020

Increased severity of the CHIMERA model induces acute vascular injury, sub-acute deficits in memory recall, and chronic white matter gliosis.

Exp Neurol 2020 02 15;324:113116. Epub 2019 Nov 15.

Djavad Mowafaghian Centre for Brain Health, Department of Pathology and Laboratory Medicine, University of British Columbia, 2215 Wesbrook Mall, Vancouver V6T 1Z3, BC, Canada. Electronic address:

Traumatic brain injury (TBI) is a leading cause of death and disability in modern societies. Diffuse axonal and vascular injury are nearly universal consequences of mechanical energy impacting the head and contribute to disability throughout the injury severity spectrum. CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) is a non-surgical, impact-acceleration model of rodent TBI that reliably produces diffuse axonal injury characterized by white matter gliosis and axonal damage. At impact energies up to 0.7 joules, which result in mild TBI in mice, CHIMERA does not produce detectable vascular or grey matter injury. This study was designed to expand CHIMERA's capacity to induce more severe injuries, including vascular damage and grey matter gliosis. This was made possible by designing a physical interface positioned between the piston and animal's head to allow higher impact energies to be transmitted to the head without causing skull fracture. Here, we assessed interface-assisted single CHIMERA TBI at 2.5 joules in wild-type mice using a study design that spanned 6 h-60 d time points. Injured animals displayed robust acute neurological deficits, elevated plasma total tau and neurofilament-light levels, transiently increased proinflammatory cytokines in brain tissue, blood-brain barrier (BBB) leakage and microstructural vascular abnormalities, and grey matter microgliosis. Memory deficits were evident at 30 d and resolved by 60 d. Intriguingly, white matter injury was not remarkable at acute time points but evolved over time, with white matter gliosis being most extensive at 60 d. Interface-assisted CHIMERA thus enables experimental modeling of distinct endophenotypes of TBI that include acute vascular and grey matter injury in addition to chronic evolution of white matter damage, similar to the natural history of human TBI.
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http://dx.doi.org/10.1016/j.expneurol.2019.113116DOI Listing
February 2020

Cerebral Microvascular Injury: A Potentially Treatable Endophenotype of Traumatic Brain Injury-Induced Neurodegeneration.

Neuron 2019 08;103(3):367-379

Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.

Traumatic brain injury (TBI) is one the most common human afflictions, contributing to long-term disability in survivors. Emerging data indicate that functional improvement or deterioration can occur years after TBI. In this regard, TBI is recognized as risk factor for late-life neurodegenerative disorders. TBI encompasses a heterogeneous disease process in which diverse injury subtypes and multiple molecular mechanisms overlap. To develop precision medicine approaches where specific pathobiological processes are targeted by mechanistically appropriate therapies, techniques to identify and measure these subtypes are needed. Traumatic microvascular injury is a common but relatively understudied TBI endophenotype. In this review, we describe evidence of microvascular dysfunction in human and animal TBI, explore the role of vascular dysfunction in neurodegenerative disease, and discuss potential opportunities for vascular-directed therapies in ameliorating TBI-related neurodegeneration. We discuss the therapeutic potential of vascular-directed therapies in TBI and the use and limitations of preclinical models to explore these therapies.
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http://dx.doi.org/10.1016/j.neuron.2019.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688649PMC
August 2019

A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer's Disease.

Sci Rep 2019 07 8;9(1):9870. Epub 2019 Jul 8.

University of British Columbia, Djavad Mowafaghian Centre for Brain Health, Vancouver, BC, V6T 2B5, Canada.

Advances in the understanding of Alzheimer's disease (AD) suggest that pathogenesis is not directly related to plaque burden, but rather to soluble toxic amyloid-beta oligomers (AßO). Therapeutic antibodies targeting Aß monomers and/or plaque have shown limited efficacy and dose-limiting adverse events in clinical trials. These findings suggest that antibodies capable of selectively neutralizing toxic AßO may achieve improved efficacy and safety. To this end, we generated monoclonal antibodies against a conformational Aß epitope predicted by computational modeling to be presented on toxic AßO but not monomers or fibrils. The resulting lead antibody, PMN310, showed the desired AßO-selective binding profile. In vitro, PMN310 inhibited AßO propagation and toxicity. In vivo, PMN310 prevented AßO-induced loss of memory formation and reduced synaptic loss and inflammation. A humanized version (huPMN310) compared favorably to other Aß-directed antibodies showing a lack of adverse event-associated binding to Aß deposits in AD brains, and greater selective binding to AßO-enriched AD brain fractions that contain synaptotoxic Aß species. Systemic administration of huPMN310 in mice resulted in brain exposure and kinetics comparable to those of other therapeutic human monoclonal antibodies. Greater selectivity for AßO and the potential to safely administer high doses of huPMN310 are expected to result in enhanced safety and therapeutic potency.
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http://dx.doi.org/10.1038/s41598-019-46306-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614461PMC
July 2019

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice.

Alzheimers Res Ther 2019 05 13;11(1):44. Epub 2019 May 13.

Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada.

Background: Alzheimer's disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice.

Methods: APP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior.

Results: In APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed.

Conclusions: ApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice.
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http://dx.doi.org/10.1186/s13195-019-0497-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515644PMC
May 2019

HDL from an Alzheimer's disease perspective.

Curr Opin Lipidol 2019 06;30(3):224-234

Department of Pathology and Laboratory Medicine.

Purpose Of Review: We review current knowledge regarding HDL and Alzheimer's disease, focusing on HDL's vasoprotective functions and potential as a biomarker and therapeutic target for the vascular contributions of Alzheimer's disease.

Recent Findings: Many epidemiological studies have observed that circulating HDL levels associate with decreased Alzheimer's disease risk. However, it is now understood that the functions of HDL may be more informative than levels of HDL cholesterol (HDL-C). Animal model studies demonstrate that HDL protects against memory deficits, neuroinflammation, and cerebral amyloid angiopathy (CAA). In-vitro studies using state-of-the-art 3D models of the human blood-brain barrier (BBB) confirm that HDL reduces vascular Aβ accumulation and attenuates Aβ-induced endothelial inflammation. Although HDL-based therapeutics have not been tested in clinical trials for Alzheimer's disease , several HDL formulations are in advanced phase clinical trials for coronary artery disease and atherosclerosis and could be leveraged toward Alzheimer's disease .

Summary: Evidence from human studies, animal models, and bioengineered arteries supports the hypothesis that HDL protects against cerebrovascular dysfunction in Alzheimer's disease. Assays of HDL functions relevant to Alzheimer's disease may be desirable biomarkers of cerebrovascular health. HDL-based therapeutics may also be of interest for Alzheimer's disease, using stand-alone or combination therapy approaches.
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http://dx.doi.org/10.1097/MOL.0000000000000604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530968PMC
June 2019

Repetitive closed-head impact model of engineered rotational acceleration (CHIMERA) injury in rats increases impulsivity, decreases dopaminergic innervation in the olfactory tubercle and generates white matter inflammation, tau phosphorylation and degeneration.

Exp Neurol 2019 07 26;317:87-99. Epub 2019 Feb 26.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address:

Traumatic brain injury (TBI) affects at least 3 M people annually. In humans, repetitive mild TBI (rmTBI) can lead to increased impulsivity and may be associated with chronic traumatic encephalopathy. To better understand the relationship between repetitive TBI (rTBI), impulsivity and neuropathology, we used CHIMERA (Closed-Head Injury Model of Engineered Rotational Acceleration) to deliver five TBIs to rats, which were continuously assessed for trait impulsivity using the delay discounting task and for neuropathology at endpoint. Compared to sham controls, rats with rTBI displayed progressive impairment in impulsive choice. Histological analyses revealed reduced dopaminergic innervation from the ventral tegmental area to the olfactory tubercle, consistent with altered impulsivity neurocircuitry. Consistent with diffuse axonal injury generated by CHIMERA, white matter inflammation, tau immunoreactivity and degeneration were observed in the optic tract and corpus callosum. Finally, pronounced grey matter microgliosis was observed in the olfactory tubercle. Our results provide insight into the mechanisms by which rTBI leads to post-traumatic psychiatric-like symptoms in a novel rat TBI platform.
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http://dx.doi.org/10.1016/j.expneurol.2019.02.012DOI Listing
July 2019

Vasoprotective Functions of High-Density Lipoproteins Relevant to Alzheimer's Disease Are Partially Conserved in Apolipoprotein B-Depleted Plasma.

Int J Mol Sci 2019 Jan 22;20(3). Epub 2019 Jan 22.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

High-density lipoproteins (HDL) are known to have vasoprotective functions in peripheral arteries and many of these functions extend to brain-derived endothelial cells. Importantly, several novel brain-relevant HDL functions have been discovered using brain endothelial cells and in 3D bioengineered human arteries. The cerebrovascular benefits of HDL in healthy humans may partly explain epidemiological evidence suggesting a protective association of circulating HDL levels against Alzheimer's Disease (AD) risk. As several methods exist to prepare HDL from plasma, here we compared cerebrovascular functions relevant to AD using HDL isolated by density gradient ultracentrifugation relative to apoB-depleted plasma prepared by polyethylene-glycol precipitation, a common high-throughput method to evaluate HDL cholesterol efflux capacity in clinical biospecimens. We found that apoB-depleted plasma was functionally equivalent to HDL isolated by ultracentrifugation in terms of its ability to reduce vascular Aβ accumulation, suppress TNFα-induced vascular inflammation and delay Aβ fibrillization. However, only HDL isolated by ultracentrifugation was able to suppress Aβ-induced vascular inflammation, improve Aβ clearance, and induce endothelial nitric oxide production.
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http://dx.doi.org/10.3390/ijms20030462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387156PMC
January 2019

Vascular dysfunction-The disregarded partner of Alzheimer's disease.

Alzheimers Dement 2019 01;15(1):158-167

Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA. Electronic address:

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.
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http://dx.doi.org/10.1016/j.jalz.2018.07.222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338083PMC
January 2019

CHIMERA repetitive mild traumatic brain injury induces chronic behavioural and neuropathological phenotypes in wild-type and APP/PS1 mice.

Alzheimers Res Ther 2019 01 12;11(1). Epub 2019 Jan 12.

Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.

Background: The annual incidence of traumatic brain injury (TBI) in the United States is over 2.5 million, with approximately 3-5 million people living with chronic sequelae. Compared with moderate-severe TBI, the long-term effects of mild TBI (mTBI) are less understood but important to address, particularly for contact sport athletes and military personnel who have high mTBI exposure. The purpose of this study was to determine the behavioural and neuropathological phenotypes induced by the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model of mTBI in both wild-type (WT) and APP/PS1 mice up to 8 months post-injury.

Methods: Male WT and APP/PS1 littermates were randomized to sham or repetitive mild TBI (rmTBI; 2 × 0.5 J impacts 24 h apart) groups at 5.7 months of age. Animals were assessed up to 8 months post-injury for acute neurological deficits using the loss of righting reflex (LRR) and Neurological Severity Score (NSS) tasks, and chronic behavioural changes using the passive avoidance (PA), Barnes maze (BM), elevated plus maze (EPM) and rotarod (RR) tasks. Neuropathological assessments included white matter damage; grey matter inflammation; and measures of Aβ levels, deposition, and aducanumab binding activity.

Results: The very mild CHIMERA rmTBI conditions used here produced no significant acute neurological or motor deficits in WT and APP/PS1 mice, but they profoundly inhibited extinction of fear memory specifically in APP/PS1 mice over the 8-month assessment period. Spatial learning and memory were affected by both injury and genotype. Anxiety and risk-taking behaviour were affected by injury but not genotype. CHIMERA rmTBI induced chronic white matter microgliosis, axonal injury and astrogliosis independent of genotype in the optic tract but not the corpus callosum, and it altered microgliosis in APP/PS1 amygdala and hippocampus. Finally, rmTBI did not alter long-term tau, Aβ or amyloid levels, but it increased aducanumab binding activity.

Conclusions: CHIMERA is a useful model to investigate the chronic consequences of rmTBI, including behavioural abnormalities consistent with features of post-traumatic stress disorder and inflammation of both white and grey matter. The presence of human Aβ greatly modified extinction of fear memory after rmTBI.
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http://dx.doi.org/10.1186/s13195-018-0461-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330571PMC
January 2019

An End-to-end System for Automatic Characterization of Iba1 Immunopositive Microglia in Whole Slide Imaging.

Neuroinformatics 2019 07;17(3):373-389

Department of Urologic Sciences, University of British Columbia, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada.

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Detailed studies of the microglial response after TBI require high throughput quantification of changes in microglial count and morphology in histological sections throughout the brain. In this paper, we present a fully automated end-to-end system that is capable of assessing microglial activation in white matter regions on whole slide images of Iba1 stained sections. Our approach involves the division of the full brain slides into smaller image patches that are subsequently automatically classified into white and grey matter sections. On the patches classified as white matter, we jointly apply functional minimization methods and deep learning classification to identify Iba1-immunopositive microglia. Detected cells are then automatically traced to preserve their complex branching structure after which fractal analysis is applied to determine the activation states of the cells. The resulting system detects white matter regions with 84% accuracy, detects microglia with a performance level of 0.70 (F1 score, the harmonic mean of precision and sensitivity) and performs binary microglia morphology classification with a 70% accuracy. This automated pipeline performs these analyses at a 20-fold increase in speed when compared to a human pathologist. Moreover, we have demonstrated robustness to variations in stain intensity common for Iba1 immunostaining. A preliminary analysis was conducted that indicated that this pipeline can identify differences in microglia response due to TBI. An automated solution to microglia cell analysis can greatly increase standardized analysis of brain slides, allowing pathologists and neuroscientists to focus on characterizing the associated underlying diseases and injuries.
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http://dx.doi.org/10.1007/s12021-018-9405-xDOI Listing
July 2019

A Rational Structured Epitope Defines a Distinct Subclass of Toxic Amyloid-beta Oligomers.

ACS Chem Neurosci 2018 07 16;9(7):1591-1606. Epub 2018 Apr 16.

Department of Medicine, Djavad Mowafaghian Centre for Brain Health , University of British Columbia , 2211 Wesbrook Mall , Vancouver , BC V6T 2B5 , Canada.

Oligomers of amyloid-β (AβO) are deemed key in synaptotoxicity and amyloid seeding of Alzheimer's disease (AD). However, the heterogeneous and dynamic nature of AβO and inadequate markers for AβO subtypes have stymied effective AβO identification and therapeutic targeting in vivo. We identified an AβO-subclass epitope defined by differential solvent orientation of the lysine 28 side chain in a constrained loop of serine-asparagine-lysine (cSNK), rarely displayed in molecular dynamics simulations of monomer and fibril ensembles. A mouse monoclonal antibody targeting AβO recognizes ∼50-60 kDa SDS-resistant soluble Aβ assemblages in AD brain and prolongs the lag phase of Aβ aggregation in vitro. Acute peripheral infusion of a murine IgG1 anti-AβO in two AD mouse models reduced soluble brain Aβ aggregates by 20-30%. Chronic cSNK peptide immunization of APP/PS1 mice engendered an anti-AβO IgG1 response without epitope spreading to Aβ monomers or fibrils and was accompanied by preservation of global PSD95 expression and improved cued fear memory. Our data indicate that the oligomer subtype AβO participates in synaptotoxicity and propagation of Aβ aggregation in vitro and in vivo.
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http://dx.doi.org/10.1021/acschemneuro.7b00469DOI Listing
July 2018

Small molecule inducers of ABCA1 and apoE that act through indirect activation of the LXR pathway.

J Lipid Res 2018 05 21;59(5):830-842. Epub 2018 Mar 21.

Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada

apoE is the primary lipid carrier within the CNS and the strongest genetic risk factor for late onset Alzheimer's disease (AD). apoE is primarily lipidated via ABCA1, and both are under transcriptional regulation by the nuclear liver X receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden. However, direct synthetic LXR ligands have hepatotoxic side effects that limit their clinical use. Here, we describe a set of small molecules, previously annotated as antagonists of the purinergic receptor, P2X7, which enhance ABCA1 expression and activity as well as apoE secretion, and are not direct LXR ligands. Furthermore, P2X7 is not required for these molecules to induce ABCA1 upregulation and apoE secretion, demonstrating that the ABCA1 and apoE effects are mechanistically independent of P2X7 inhibition. Hence, we have identified novel dual activity compounds that upregulate ABCA1 across multiple CNS cell types, including human astrocytes, pericytes, and microglia, through an indirect LXR mechanism and that also independently inhibit P2X7 receptor activity.
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http://dx.doi.org/10.1194/jlr.M081851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928439PMC
May 2018

Age at injury and genotype modify acute inflammatory and neurofilament-light responses to mild CHIMERA traumatic brain injury in wild-type and APP/PS1 mice.

Exp Neurol 2018 03 18;301(Pt A):26-38. Epub 2017 Dec 18.

Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address:

Peak incidence of traumatic brain injury (TBI) occurs in both young and old individuals, and older age at injury is associated with worse outcome and poorer recovery. Moderate-severe TBI is a reported risk factor for dementia, including Alzheimer's disease (AD), but whether mild TBI (mTBI) alters AD pathogenesis is not clear. To delineate how age at injury and predisposition to amyloid formation affect the acute response to mTBI, we used the Closed Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model of TBI to induce two mild injuries in wild-type (WT) and APP/PS1 mice at either 6 or 13months of age and assessed behavioural, histological and biochemical changes up to 14days post-injury. Age at injury did not alter acute behavioural responses to mTBI, including measures of neurological status, motor performance, spatial memory, fear, or anxiety, in either strain. Young APP/PS1 mice showed a subtle and transient increase in diffuse Aβ deposits after injury, whereas old APP/PS1 mice showed decreased amyloid deposits, without significant alterations in total soluble or insoluble Aβ levels at either age. Age at injury and genotype showed complex responses with respect to microglial and cytokine outcomes, where post-injury neuroinflammation is increased in old WT mice but attenuated in old APP/PS1 mice. Intriguingly, silver staining confirmed axonal damage in both strains and ages, yet only young WT and APP/PS1 mice showed neurofilament-positive axonal swellings after mTBI, as this response was almost entirely attenuated in old mice. Plasma neurofilament-light levels were significantly elevated after injury only in young APP/PS1 mice. This study suggests that mild TBI has minimal effects on Aβ metabolism, but that age and genotype can each modify acute outcomes related to white matter injury.
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http://dx.doi.org/10.1016/j.expneurol.2017.12.007DOI Listing
March 2018

Clearance of beta-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels.

Elife 2017 10 10;6. Epub 2017 Oct 10.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.

Amyloid plaques, consisting of deposited beta-amyloid (Aβ), are a neuropathological hallmark of Alzheimer's Disease (AD). Cerebral vessels play a major role in AD, as Aβ is cleared from the brain by pathways involving the cerebrovasculature, most AD patients have cerebrovascular amyloid (cerebral amyloid angiopathy (CAA), and cardiovascular risk factors increase dementia risk. Here we present a notable advance in vascular tissue engineering by generating the first functional 3-dimensioinal model of CAA in bioengineered human vessels. We show that lipoproteins including brain (apoE) and circulating (high-density lipoprotein, HDL) synergize to facilitate Aβ transport across bioengineered human cerebral vessels. These lipoproteins facilitate Aβ42 transport more efficiently than Aβ40, consistent with Aβ40 being the primary species that accumulates in CAA. Moreover, apoE4 is less effective than apoE2 in promoting Aβ transport, also consistent with the well-established role of apoE4 in Aβ deposition in AD.
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http://dx.doi.org/10.7554/eLife.29595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634784PMC
October 2017

High-density lipoproteins suppress Aβ-induced PBMC adhesion to human endothelial cells in bioengineered vessels and in monoculture.

Mol Neurodegener 2017 08 22;12(1):60. Epub 2017 Aug 22.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.

Background: Alzheimer's Disease (AD), characterized by accumulation of beta-amyloid (Aβ) plaques in the brain, can be caused by age-related failures to clear Aβ from the brain through pathways that involve the cerebrovasculature. Vascular risk factors are known to increase AD risk, but less is known about potential protective factors. We hypothesize that high-density lipoproteins (HDL) may protect against AD, as HDL have vasoprotective properties that are well described for peripheral vessels. Epidemiological studies suggest that HDL is associated with reduced AD risk, and animal model studies support a beneficial role for HDL in selectively reducing cerebrovascular amyloid deposition and neuroinflammation. However, the mechanism by which HDL may protect the cerebrovascular endothelium in the context of AD is not understood.

Methods: We used peripheral blood mononuclear cell adhesion assays in both a highly novel three dimensional (3D) biomimetic model of the human vasculature composed of primary human endothelial cells (EC) and smooth muscle cells cultured under flow conditions, as well as in monolayer cultures of ECs, to study how HDL protects ECs from the detrimental effects of Aβ.

Results: Following Aβ addition to the abluminal (brain) side of the vessel, we demonstrate that HDL circulated within the lumen attenuates monocyte adhesion to ECs in this biofidelic vascular model. The mechanism by which HDL suppresses Aβ-mediated monocyte adhesion to ECs was investigated using monotypic EC cultures. We show that HDL reduces Aβ-induced PBMC adhesion to ECs independent of nitric oxide (NO) production, miR-233 and changes in adhesion molecule expression. Rather, HDL acts through scavenger receptor (SR)-BI to block Aβ uptake into ECs and, in cell-free assays, can maintain Aβ in a soluble state. We confirm the role of SR-BI in our bioengineered human vessel.

Conclusion: Our results define a novel activity of HDL that suppresses Aβ-mediated monocyte adhesion to the cerebrovascular endothelium.
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http://dx.doi.org/10.1186/s13024-017-0201-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568306PMC
August 2017

Frontal Traumatic Brain Injury Increases Impulsive Decision Making in Rats: A Potential Role for the Inflammatory Cytokine Interleukin-12.

J Neurotrauma 2017 10 24;34(19):2790-2800. Epub 2017 May 24.

1 Djavad Mowafaghian Centre for Brain Health, University of British Columbia , Vancouver, British Columbia, Canada .

Traumatic brain injury (TBI) is associated with the development of numerous psychiatric diseases. Of particular concern for TBI patients is the impact of chronic impulsivity on daily functioning. Despite the scope of the human problem, little has been done to address impulsivity in animal models of brain injury. In the current study, we examined the effects of either a severe or a milder bilateral frontal controlled cortical impact injury on impulsivity using the Delay Discounting Task (DDT), in which preference for smaller-sooner over larger-later rewards is indicative of greater impulsive choice. Both milder and severe TBI caused a significant, chronic increase in impulsive decision making. Despite these pronounced changes in performance of the DDT, memory function, as assessed by the Morris Water Maze, was not impaired in more mildly injured rats and only transiently impacted in the severe TBI group. Whereas a significant lesion was only evident in severely injured rats, analysis of cytokine levels within the frontal cortex revealed a selective increase in interleukin (IL)-12 that was associated with the magnitude of the change in impulsive choice caused by both milder and severe TBI. These findings suggest that tissue loss alone cannot explain the increased impulsivity observed, and that inflammatory pathways mediated by IL-12 may be a contributing factor. The findings from this study highlight the sensitivity of sophisticated behavioral measures designed to assess neuropsychiatric dysfunction in the detection of TBI-induced cognitive impairments and their utility in identifying potential mechanistic pathways and therapeutic targets.
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http://dx.doi.org/10.1089/neu.2016.4813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647497PMC
October 2017

Defining the biomechanical and biological threshold of murine mild traumatic brain injury using CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration).

Exp Neurol 2017 06 6;292:80-91. Epub 2017 Mar 6.

Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada; International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) is a recently described animal model of traumatic brain injury (TBI) that primarily produces diffuse axonal injury (DAI) characterized by white matter inflammation and axonal damage. CHIMERA was specifically designed to reliably generate a variety of TBI severities using precise and quantifiable biomechanical inputs in a nonsurgical user-friendly platform. The objective of this study was to define the lower limit of single impact mild TBI (mTBI) using CHIMERA by characterizing the dose-response relationship between biomechanical input and neurological, behavioral, neuropathological and biochemical outcomes. Wild-type male mice were subjected to a single CHIMERA TBI using six impact energies ranging from 0.1 to 0.7J, and post-TBI outcomes were assessed over an acute period of 14days. Here we report that single TBI using CHIMERA induces injury dose- and time-dependent changes in behavioral and neurological deficits, axonal damage, white matter tract microgliosis and astrogliosis. Impact energies of 0.4J or below produced no significant phenotype (subthreshold), 0.5J led to significant changes for one or more phenotypes (threshold), and 0.6 and 0.7J resulted in significant changes in all outcomes assessed (mTBI). We further show that linear head kinematics are the most robust predictors of duration of unconsciousness, severity of neurological deficits, white matter injury, and microgliosis following single TBI. Our data extend the validation of CHIMERA as a biofidelic animal model of DAI and establish working parameters to guide future investigations of the mechanisms underlying axonal pathology and inflammation induced by mechanical trauma.
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http://dx.doi.org/10.1016/j.expneurol.2017.03.003DOI Listing
June 2017