Cheryl Lea Wellington


Relevant Thesis-Based Degree Programs


Open Research Positions

This list of possible research projects is non-exhaustive. It only shows positions that are specifically advertised in the G+PS website.

Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Translational modelling of traumatic axonal and vascular injury using CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) (2020)

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 are major contributors to disability throughout the spectrum of injury severity. Designing a rodent model of head injury that recapitulates the hallmarks of human TBI is important to delineate biological mechanisms of TBI, to help pinpoint targets for future therapeutic strategies. We developed CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration), a non-surgical, impact-acceleration model of rodent TBI that reliably produces diffuse axonal injury characterized by white matter inflammation and axonal damage at 0.5J. In this thesis, we begin by investigating the behavioral and neuropathological phenotypes induced by single CHIMERA TBI up to 0.7J. We demonstrate the capability of CHIMERA to induce proportionate outcomes based on biomechanical inputs, as single CHIMERA TBI at 0.6 and 0.7J in wild-type mice induced neurological and motor deficits, and triggered white matter damage and inflammation in a dose-dependent manner. Subsequently, we expanded CHIMERA’s capacity to induce more severe injuries with evidence of vascular damage and grey matter inflammation, in the hopes that therapies can be developed for TBIs across the injury spectrum. We report that interface-assisted single CHIMERA TBI at 2.5J in wild-type mice induced neurological deficits, elevated plasma total tau and neurofilament-light levels, transiently increased proinflammatory cytokines in brain, blood-brain barrier leakage and vascular abnormalities, as well as grey matter microgliosis. Finally, we expanded the CHIMERA platform to rats, to better understand the relationship between repetitive TBI (rTBI), impulsivity and neuropathology. Compared to sham controls, rats with rTBI displayed progressive impairment in impulsive choice. In addition to histological changes sustained by the mesolimbic dopaminergic system, grey and white matter inflammation along with tau immunoreactivity were observed. In summary, we have developed a valuable rodent model of human TBI, replicating many of the hallmarks of clinical and neuropathological TBI in both mouse and rat models. We therefore hope that this platform can be used to validate promising drug targets that may ameliorate the inflammatory and behavioral sequelae of human TBI.

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Vasoprotective functions of high-density lipoproteins on the cerebrovasculature and their relevance for Alzheimer's disease (2020)

One in eleven Canadians over the age of 65 suffers from dementia, the most common form being Alzheimer’s disease (AD). AD has traditionally been characterized by the presence of amyloid beta (Aβ) plaques and neurofibrillary tangles and in more recent years also by neuroinflammation and cerebrovascular dysfunction. We hypothesize that circulating high-density lipoproteins (HDL) may protect against such cerebrovascular dysfunction and inflammation to reduce AD risk. HDL in healthy people is already known to have several vasoprotective functions on cells in peripheral arteries and higher levels of HDL cholesterol (HDL-C) or apolipoprotein A-I (apoA-I), its primary protein component, in blood are associated with reduced AD risk. Furthermore, studies in AD transgenic mouse models suggest that HDL protects against vascular Aβ deposition, memory deficits, and neuroinflammation. This thesis used mouse models and in vitro human cellular models to extend the current knowledge on the protective effects of HDL against AD.First, transgenic AD mice were employed to further investigate the role of HDL on cerebrovascular-specific pathologies in AD using a genetic approach and a pharmacological approach. Genetic loss of apoA-I in AD transgenic mice exacerbated vascular Aβ deposition, activation of cerebrovascular endothelial cell and vessel-associated astrocytes, global amyloid burden, neuroinflammation, and cognitive deficits. Pharmacological modulation of cholesterol metabolism exclusively outside of the brain resulted in reduced neuroinflammation, activation of cerebrovascular endothelial cells, and cognitive deficits. Next, 2-dimensional (2D) in vitro cell cultures of human brain-derived endothelial cells (EC) and 3D bioengineered human arteries were used to show that several of the known vasoprotective functions of HDL extend to brain cells and that HDL has novel protective functions against Aβ vascular deposition and Aβ-induced vascular inflammation in bioengineered tissues. Finally, efforts were made to develop high-throughput assays of these novel HDL functions in order to evaluate whether these functions are lost in people with AD or AD risk factors. In summary, this thesis suggests novel pathways by which circulating HDL can promote cerebrovascular health using in vivo and in vitro models and suggests that improving the levels of functional HDL may be a valuable therapeutic or preventative strategy for AD.

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The interaction of repetitive mild traumatic brain injury, Alzheimer disease and ageing (2018)

Traumatic brain injury (TBI) is an important public health issue worldwide. It is strongly linked to neurodegenerative conditions such as Alzheimer’s Disease (AD) and Chronic Traumatic Encephalopathy. Despite numerous promising pre-clinical studies, there is no effective clinical treatment for TBI, indicating inefficiency in translation of scientific research from bench to bedside.This thesis thus attempts to address the issue through two approaches. Firstly, we reviewed the commonly-used pre-clinical TBI models, and found that many lack thorough biomechanical considerations. We thus developed a new mouse TBI model, Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA). CHIMERA reproducibly induces clinically-relevant TBI, both in terms of biomechanics and neuropathology. CHIMERA mild TBI (mTBI) induces behavioural (e.g. neurological, motor, and cognitive), histological and biochemical changes (e.g. diffuse axonal injury, white matter microgliosis, and brain cytokine induction). We further demonstrated that CHIMERA mTBI outcomes are scalable by varying the mechanical inputs. These observations demonstrate that CHIMERA is a novel and valuable platform for TBI research.Next, we induced CHIMERA mTBI in APP/PS1 mice, a transgenic model of AD amyloidosis, and characterised both acute and long-term consequences. Here we included two age groups of animals, as TBI occur in both the young and the old populations. In the acute phase, mTBI led to subtle and transient age-dependent changes in A-beta deposits. Age-at-injury and genotype showed complex interactions in determining microglial and cytokine outcomes, such that neuroinflammation was increased in old wildtype mice and young APP/PS1 mice. Age-at-injury also markedly affected neurofilament response, as neurofilament-positive axonal bulbs and plasma neurofilament-light levels were elevated in young mice, but not old mice, of both genotypes. In the chronic phase, mTBI led to prolonged white matter microgliosis and axonal injury up to 8-mo post-injury. MTBI also intensified long-term fear memory in APP/PS1 mice, reminiscent of post-traumatic stress disorder phenotypes.In summary, we have developed a reproducible and clinically-relevant TBI model. We showed that genetic predisposition to AD and age-at-injury are both significant modifiers of acute and long-term mTBI outcomes. These findings may provide insights for future attempts in understanding the mechanistic pathways of TBI pathogenesis.

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The Role of Apolipoprotein E in Recovery from Traumatic Brain Injury and Development of CHIMERA: A Novel Closed-Head Impact Model of Engineered Rotational Acceleration (2015)

Traumatic brain injury (TBI) is a “silent epidemic” that currently lacks any effective treatment. While a major health care problem in itself, TBI also increases Alzheimer’s disease (AD) risk and leads to the deposition of neurofibrillary tangles and amyloid deposits similar to those found in AD. Agonists of Liver X receptors (LXRs), which regulate the expression of many genes involved in lipid homeostasis and inflammation, improve cognition and reduce neuropathology in AD mice. One pathway by which LXR agonists exert their beneficial effects is through ATP-binding cassette transporter A1-mediated lipid transport onto apolipoprotein E (apoE). In the first part of this thesis, I show that a short-term treatment with synthetic LXR agonist GW3965 improves post-injury outcomes in mice subjected to closed-head, mild, repetitive weight drop TBI (mrTBI). My results suggest that both apoE-dependent and apoE-independent pathways contribute to the ability of GW3965 to promote recovery from mrTBI. While many drugs have shown promising outcomes in preclinical TBI models, clinical drug trials for TBI so far have failed, suggesting that the translational potential of TBI models may require further improvement. As most human TBIs result from impact to an intact skull, closed head injury (CHI) rodent models are highly relevant. Traditional CHI models like weight drop however suffer from large experimental variability that may be due to poor control over biomechanical inputs. To address this caveat we developed a novel CHI model called CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration) that fully integrates biomechanical, behavioral, and neuropathological analyses. CHIMERA is distinct from existing neurotrauma model systems in that it uses a completely non-surgical procedure to precisely deliver impacts of prescribed dynamic characteristics to a closed skull while enabling kinematic analysis of unconstrained head movement. Here I show that repeated TBI in mice using CHIMERA mimics many features of the human TBI including neurological, motor, and cognitive deficits along with persistent neuroinflammation and diffuse axonal injury, and increased endogenous tau phosphorylation up to 14 days with a reliable biomechanical response of the head. This makes CHIMERA well suited to investigate the pathophysiology of TBI and for drug development programs.

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Regulation and transport of apolipoprotein A-I into the central nervous system and therapeutic potential in Alzheimer's disease (2014)

Patients with Alzheimer’s Disease (AD) exhibit substantial cerebrovascular damage, including the accumulation of β-amyloid (Aβ) peptides within the vessel wall. Mid-life vascular risk factors increase the risk of AD potentially via the loss of beneficial or gain of toxic functions in circulating high density lipoprotein (HDL). Low plasma levels of apolipoprotein A-I (apoA-I), the primary protein component of HDL, increase AD risk and correlate with cognitive decline, and preliminary preclinical evidence supports a role of apoA-I in mediating removal of cerebrovascular Aβ, suppressing neuroinflammation, and enhancing cognitive function. Our strategy was to perturb peripheral and central nervous system (CNS) apoA-I levels through genetic modification of proteins known to regulate apoA-I metabolism and via indirect and direct pharmacological manipulation of apoA-I to delineate its CNS transport, regulation and therapeutic potential in AD. Loss of ATP binding cassette transporter A1 (ABCA1), which effluxes cholesterol onto lipid-poor apoA-I to generate immature pre-β-HDL, lead to significant parallel decreases of circulating and CNS apoA-I, while stimulation of ABCA1 activity with an Liver-X-Receptor (LXR) agonist substantially increased apoA-I levels selectively in the CNS, solubilized Aβ and improved cognitive function in AD mice. Although apoA-I was increased independent of ABCA1, ABCA1 was required to observe LXR-mediated cognitive benefits, suggesting lipidation of apolipoproteins is a critical regulator of their function. Pre-β-HDL appear to be the more biologically relevant species regarding CNS health, as loss of lecithin-cholesterol acetyl transferase (LCAT), which esterifies free cholesterol to generate mature α-HDL, does not impact AD pathology in vivo. Intravenously injected human apoA-I gains access to the CNS predominantly via the blood cerebrospinal fluid barrier, where it is bound, internalized, and transported by the epithelial cells of the choroid plexus in a specific receptor mediated fashion. Weekly injection of reconstituted HDL, formulated to enrich the pre-β pool, into symptomatic AD mice transiently decreased plasma Aβ levels but was unable to modulate brain Aβ, neuroinflammation, or endothelial activation in the experimental paradigm used. Collectively, these data identified ABCA1 generated apoA-I pre-β-HDL species as a key population of HDL subspecies for modulating AD pathology in vivo.

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Regulation of apolipoprotein E secretion, lipidation and recycling in the central nervous system (2014)

Lipid transport in the brain is coordinated by glia-derived lipoproteins that contain apolipoprotein E (apoE) as their primary protein. ApoE plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). ATP-binding cassette transporter A1 (ABCA1) effluxes cholesterol and phospholipids to apolipoprotein acceptors including apoE. ABCA1 is a key regulator of apoE levels and lipidation in the brain and deficiency of ABCA1 increases amyloid burden in AD mouse models. Translating these findings to potential therapies for AD will require a more thorough understanding of the biochemical nature of nascent apoE particles generated from glia and of lipoprotein remodeling in the CNS in general. In this thesis, I show that apoE is secreted from wild-type primary murine mixed glia as nascent lipoprotein subspecies ranging from 7.5 to 17 nm in diameter. Glia lacking ABCA1 secrete only one species of small particles (~8.1nm), which are poorly lipidated, but can accept lipids to form the full repertoire of wild-type apoE particles. Inhibition of apoE receptor function blocks appearance of the 8.1 nm species, suggesting that this particle may arise through apoE recycling. Selective deletion of the LDL receptor significantly reduces the level of the 8.1 nm particles, suggesting that apoE is preferentially recycled through LDLR. These results suggest that nascent glial apoE lipoproteins are secreted through multiple pathways.Modulating the expression, secretion or function of apoE may provide potential therapeutic approaches to protect the brain from chronic and acute damage. This thesis shows that progesterone and a synthetic progestin, lynestrenol, significantly induce apoE secretion from human CCF-STTG1 astrocytoma cells, whereas estrogens have negligible effects. Intriguingly, lynestrenol also increases expression of ABCA1 in human astrocytoma cells, primary murine glia, and immortalized murine astrocytes that express human apoE3. The progesterone receptor (PR) inhibitor RU486 attenuates the effect of progestins on apoE expression in astrocytoma but has no effect on ABCA1 expression in all glial cell models tested, suggesting that PR may participate in apoE but does not affect ABCA1 regulation. These results suggest that selective reproductive steroid hormones have the potential to influence glial lipid homeostasis through LXR-dependent and PR-dependent pathways.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Conceptualization and development of in vitro vascular models for studying Alzheimer's Disease (2022)

The human brain is an extraordinarily complex organ that is regulated by the input of nutrients and oxygen and the removal of waste via the vascular network. Understanding how the local microenvironment of cells that make up the neurovascular unit influences the health of the human brain could allow for better understanding of disease pathology, such as Alzheimer’s Disease (AD). Traditional animal-based models are limited in some of their physiological similarities with humans; therefore, human-based in vitro models are desirable. Standard cell culture is often performed in a 2-dimensional, static well plate, which lacks many of the physiological properties seen in the human brain. Moving towards in vitro models that include defined cellular architectures and includes flow on the endothelial cell layer could overcome some of the challenges associated with standard well plate models. In this thesis, in vitro models of the capillary and arteriole are conceptualized and developed. Two capillary-based microfluidic designs are developed, with a focus on the fabrication techniques used for the master molds, as well as the endothelial cell layer optimization. Having a tight endothelial cell layer is important to ensure that transport into and out of the brain is based on transcellular transport and not due to a leaky barrier. The first capillary model described includes a hydrogel-based extracellular matrix, and the second contains a planar membrane acting as a substrate for the endothelial cell barrier. In addition, this work highlights improvements to a previously used tissue chamber that contains a cell-laden scaffold. The motivation for these improvements includes the fragility of the tissue chamber and only being able to perform in-line sampling from the circulating fluid within the “blood” side, limiting the ability to perform in-line vessel transport studies. The fabrication of custom end-caps, to improve the tissue chamber stability, and the inclusion of sampling ports to the “brain” side are also described.

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Evaluation of serum neurofilament light chain as a diagnostic and prognostic biomarker in traumatic brain injury (2021)

Background: Traumatic brain injury (TBI) is a leading cause of death and disability and can cause mild, moderate, or severe injury. TBI occurs mostly in youth and in seniors, demonstrating the importance of understanding how age at injury affects TBI diagnosis and prognosis. Although most TBI studies focus on youth, seniors have high TBI incidence mainly from falls. Considerable research has identified serum neurofilament light (NF-L) as a sensitive marker of axonal injury, however, little is known about its diagnostic and prognostic utility in geriatric TBI. This study was designed to evaluate the diagnostic potential of NF-L for mild TBI and the potential of NF-L to predict outcome at 12-months after injury across the lifespan, using the Glasgow Outcome Scale-Extended (GOS-E).Methods: Blood specimens from TBI subjects (N=244; median age=46y) and age-matched trauma controls (TC) (N=128; median age=40y) were collected within 24 hours of injury, with additional specimens collected on days 4, 7, 14 and 28 wherever possible. Serum NF-L was quantified using Quanterix single molecule array assays. Logistic regression analyses were performed for diagnostic and prognostic models. Receiver operating characteristic (ROC) curve analysis was performed to assess diagnostic utility. Multiple imputations were performed for GOS-E prior to assessing prognostic utility.Results: Acute median serum NF-L levels were significantly elevated in mild and moderate-severe TBI (11.3 pg/mL and 78.6 pg/mL; p60y. Longitudinally, serum NF-L increased over time, peaking at 14 days, and remaining elevated at 28 days. Acute median serum NF-L correlated with GOS-E (rho=-0.476), with significantly higher levels in subjects predicted to have poor (GOS-E
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AXL receptor tyrosine kinase regulates Apolipoprotein E expression (2018)

Alzheimer's disease (AD), the leading cause of dementia, is a chronic neurodegenerative disease. One of the hallmarks of AD is the accumulation of amyloid plaques in the brain. Apolipoprotein E (apoE), which carries lipids in the brain in the form of lipoproteins, plays an undisputed role in AD pathophysiology. The APOE gene is the most validated genetic risk factor for late onset AD, and has well-established associations with amyloid deposition and clearance from the brain. We and others have shown that lipidation of apoE can assist amyloid clearance, raising interest in augmenting apoE function as a proposed therapeutic strategy for AD. A high-throughput phenotypic screen was conducted using a CCF-STTG1 human astrocytoma cell line to identify small molecules that could upregulate apoE secretion. A subset of AXL receptor tyrosine kinase inhibitors, which we term AXL modulators were identified as positive hits. The objective of this thesis is to dissect the mechanism of action (MoA) by which AXL modulators upregulate apoE expression. We initially understood their dependency on AXL by treating AXL-/- CCF-STTG1 cells generated using CRISPR-Cas9 method with the lead compound. We then determined if Liver X Receptor (LXR) activity was required utilizing LXR knock-out (KO) mouse embryonic fibroblasts (MEF) cells. Immunoblotting analysis of AXL protein indicated the ability of AXL modulators to promote AXL receptor cleavage and stabilize the intracellular domain (ICD). To investigate the role of AXL-ICD in apoE homeostasis, various Axl variants, including WT AXL, kinase-dead AXL mutant, Axl-ICD, and AXL N-terminal fragment were stably reconstituted in AXL-/- CCF-STTG1 cells. ApoE baseline expression was significantly upregulated only upon reconstitution of ICD-containing AXL variants. In summary, AXL protein plays a significant role in apoE homeostasis through its intracellular domain.

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The role of lipoproteins on selected functions relevant to Alzheimer's Disease in human brain perivascular cells (2018)

Alzheimer‘s Disease (AD) is a progressive neurodegenerative disease that affects millions ofpeople world-wide. It is characterized by amyloid plaques and neurofibrillary tangles in thebrain. Many AD patients also show loss of cerebrovascular integrity, which is thought to lead todecreased capillary flow, neuronal injury and impaired clearance of amyloid beta. Sinceapolipoprotein E (apoE) and high density lipoprotein (HDL) show many beneficial effects in thevasculature in the body, we aimed to test the effects of these lipoproteins on primary humanperivascular cells in the brain. We found that pharmacologically increasing apoE levels withGW3965 in a scratch-wound assay was not associated with changes in pericyte migration.Interestingly, we found that Axl inhibitor A1 slowed pericyte migration without showingchanges in secreted apoE levels, suggesting an apoE-independent pathway for pericytemigration. We also tested whether HDL can attenuate the CypA-NFκB-MMP9 inflammatorypathway associated with apoE4 pericytes, but failed to observe the activation of thisinflammatory pathway in our pericytes. Lastly, we found that when macrophages were treatedwith HDL, Aβ phagocytosis was not changed. Moreover, there were donor differences in theinflammatory response of macrophages to Aβ, making consistent observations difficult. Takentogether, we did not show beneficial effects of lipoproteins on perivascular cell function in thecontext of AD.

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