Relevant Degree Programs
Affiliations to Research Centres, Institutes & Clusters
Alzheimer's disease; Down syndrome; neuropsychiatric disorders; Neurogenesis.
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Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Nov 2020)
Deposition of the amyloid β protein (Aβ) into neuritic plaques is the neuropathological hallmark of Alzheimer's Disease (AD). Aβ is generated through the cleavage of the Amyloid Precursor Protein (APP) by β-secretase and γ-secretase. Currently, the evaluation of APP cleavage by β-secretase in experimental settings has largely depended on models that do not replicate the physiological conditions of this process. We have developed a chimeric protein construct, ASGβ, incorporating the β-site cleavage sequence of APP targeted by β-secretase and its intracellular trafficking signal into a Phosphatase-eGFP secreted reporter system. Upon cleavage by β-secretase, ASGβ releases a phosphatase-containing portion that can be measured in the culture medium, and an intracellular fraction that can be detected through western blot. Subsequently, we have generated a cell line stably expressing ASGβ that can be utilized to assay β-secretase in real time. Our findings suggest this system could be a high-throughput tool to screen compounds that aim to modulate β-secretase activity and Aβ production under physiological conditions, as well as evaluating factors that regulate this cleavage.Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described and more recently we have identified novel mutations in 2 genes, NLRP12 and NCOA3 in familial forms of the disease. Our findings show that one of the discovered mutations on NLRP12 affects the maturation of Caspase-1, and that the mutation discovered on NCOA3 leads to a higher basal level of inducible Nitric Oxide Synthase (iNOS). These findings show novel mechanisms causing the disruption of immune and inflammatory responses that could in turn lead to the symptoms observed in MS patients. Our study suggests that further characterization of the pathways affected by the NLRP12 and NCOA3 could lead to a better understanding of the phenomena causing MS, and the development of novel, more effective treatments for the treatment of symptoms.
Down syndrome (DS) is the most common genetic cause of intellectual disabilities. Trisomy 21, an extra copy of human chromosome 21, causes the majority of DS cases. After middle age, individuals with DS inevitably develop Alzheimer’s disease, the most common form of neurodegenerative diseases characterized by extracellular amyloid plaque deposition, intracellular neuritic fibrillary tangles and neuronal loss. The extracellular amyloid plaques are made of amyloid β (Aβ) proteins derived from β- and γ- cleavage of amyloid precursor protein (APP). The abnormal accumulation of Aβ proteins plays an essential role in AD pathogenesis. Ubiquitin-specific protease 25 (USP25) is a deubiquitinating enzyme that locates in the DS critical region of human chromosome 21. It is overexpressed in DS patients and has been shown involved in a variety of cellular processes, including immunity, myogenesis and protein degradation. However, the potential role of USP25 in neurodegenerative diseases has not been examined yet. This thesis entails an examination of the role of USP25 in the pathogenesis of Alzheimer’s disease in Down Syndrome. First, we investigated the transcriptional regulation of human USP25 gene. We identified a functional SP1 binding site within its 5’ promoter region. We found that Sp1 signaling up-regulated USP25 transcription. Then we showed that USP25 affected APP processing by slowing down the degradation of APP and BACE1. It also altered the intracellular trafficking of BACE1 and promoted C-terminal fragment (CTF) production, indicating its role in amyloidogenic pathway in AD pathogenesis. In the third chapter, we examined the effects of USP25 on neuronal survival and proliferation. We found that USP25 overexpression facilitated oxidative stress-induced cell death and caspase-3 activation through inhibiting NF-κB activation. It upregulation also affects cell cycle regulation both during embryonic neurogenesis and adulthood cortical development. In summary, this study investigated the effect of USP25 in the development of AD in DS. It demonstrated for the first time that USP25 overexpression contributes to the development of AD pathology by regulating APP processing, affecting neurogenesis. Our findings indicated that USP25 may serve as a potential pharmacological target for treating AD specifically in DS.
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are featured by cholinergic and dopaminergic neuron loss, respectively. As a unique pathological hallmark of AD, neuritic plaques contain aggregated amyloid β protein (Aβ), generated from amyloid β precursor protein (APP). APP mutations cause familial AD; mutations in the alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2) genes are associated with PD. Recent studies suggest that the level of LRRK2 affects its toxicity in neurons. Therefore, understanding the mechanisms underlying LRRK2 expression would help to examine its pathogenic effects on PD. However, the features of the LRRK2 promoter remain elusive. In the first project, we cloned and characterized the LRRK2 promoter. There were two functional cis-acting specificity protein 1(Sp1)-responsive elements in its promoter. Our study demonstrates that LRRK2 transcription and translation were facilitated by Sp1 overexpression and blocked by an Sp1 inhibitor in vitro.The Lewy bodies primarily consist of α-synuclein protein, encoded by SNCA, and SNCAA₅₃T mutation promotes α-synuclein aggregation. The Swedish APP mutation (APPSWE) promotes Aβ generation and AD pathogenesis. However, the mechanisms underlying selective neurodegeneration in AD and PD are still unknown. In the second project, we stably overexpressed wildtype and mutated APP and SNCA genes in cholinergic SN56 and dopaminergic MN9D cells. APPSWE and SNCAA₅₃T mutations enhanced Aβ generation and α-synuclein inclusion formation in SN56 and MN9D cells, respectively. Aβ₄₂ and mutant α-synuclein oligomers caused severe cell death in SN56-APPSWE and MN9D-SNCAA53T cells, respectively. Furthermore, syndecan 3 (SDC3) and fibroblast growth factor receptor like 1 (FGFRL1) genes were identified as two of the differentially expressed genes in APP- and SNCA- related stable cells by microarrays. SDC3 was increased in the cholinergic nucleus of APPSWE knock-in mouse brains, whereas FGFRL1 was elevated in dopaminergic neurons in SNCAA₅₃T transgenic mice. Finally, knockdown of SDC3 and FGFRL1 attenuated oxidative stress-induced cell death in SN56-APPSWE and MN9D-SNCAA₅₃T cells. Overall, these demonstrate that SDC3 and FGFRL1 mediated the specific effects of APPSWE and SNCAA₅₃T on cholinergic and dopaminergic neurodegeneration in AD and PD, respectively. Our study suggests that SDC3 and FGFRL1 could be potential targets to alleviate the selective neurodegeneration in AD and PD.
As a pleiotropic protein, macrophage migration inhibitory factor (MIF) participates in many cellular activities including inflammatory response, energy metabolism, and apoptosis. Dysregulation of MIF has been associated with chronic inflammatory conditions, and inhibition of its activity has been proposed as a therapeutic strategy. However, MIF gene knockout shows detrimental effects under stress-induced acute conditions such as infection and ischemia/reperfusion (I/R). Compared to a large body of research regarding the role of MIF outside of the central nervous system, limited studies have been carried out to address its role in neurological conditions. Previous studies showed that MIF protects cardiomyocytes from I/R induced detrimental effects. Since strokes are detrimental to neurons in a similar way that heart attacks are to cardiomyocytes, MIF may exert similar effects to protect neurons. Therefore, we aimed to study the regulation of MIF expression and its potential role in strokes. We identified two functional cis-acting NFκB binding elements on the MIF gene promoter and demonstrated that NFκB regulates MIF expression by transcriptional activation of the MIF gene promoter via these two sites. Under hypoxic conditions, MIF gene transcription is reduced by activation of NFκB signaling, which contributes to the down-regulation of MIF expression in the ischemic territory during strokes. We further demonstrated that MIF reduces caspase-3 activation and protects neurons from oxidative stress-induced and I/R-induced apoptosis in vitro. Using a stroke model, we showed that MIF gene knockout results in elevated caspase-3 activation, exacerbates neuronal death, and accelerates infarct development. These results suggest that MIF exhibits neuroprotective effects following a stroke. As stroke increases the risk of developing Alzheimer’s disease (AD), we further evaluated whether MIF could serve as a molecular link between stroke and AD by exploring the expression profile of MIF and its role in AD. We have provided first-hand evidence suggesting that elevation of MIF expression is induced by a pathological increase of Aβ deposits at the late stage of AD, but this effect does not recover its role in mediating normal behavioral functions in AD, because it is sequestered on the Aβ deposits in a loss-of-function fashion.
Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the unique pathological feature of Alzheimer’s disease (AD). Aβ is derived from the cleavages of amyloid β precursor protein (APP) by β-secretase at Asp-1 site and by γ-secretase. Beta-site APP cleaving enzyme 1 (BACE1) is the β-secretase. It mainly cleaves APP within the Aβ region at the Glu-11 site to generate truncated Aβ species. Twenty-one kilodalton transmembrane trafficking protein, TMP21 (also named TMED10, p23) is a vesicular trafficking protein and a member of p24 family proteins. TMP21 mediates protein endoplasmic reticulum (ER)/Golgi transport and selectively guides the glycosylphosphatidylinositol-anchored proteins into lipid rafts. It is also essential for forming Golgi structural organization. Recent studies show that the downregulation of TMP21 increases Aβ generation by affecting APP trafficking and selectively modulating γ-cleavage on APP. However, the precise roles of TMP21 in AD pathogenesis remain unknown.In this thesis, we reported the discovery of a novel AD-associated single nucleotide polymorphism (SNP) in the intron 4 of Tmp21. This SNP significantly increases TMP21 transcript splicing efficiency in vitro, resulting in upregulation of TMP21 gene expression. Furthermore, we found that overexpression of TMP21 shifts APP processing from the non-amyloidogenic to the amyloidogenic pathway by specifically increasing the BACE1 activity at Asp-1 site. Downregulation of TMP21 also facilitates amyloidogenic cleavage. The interaction between TMP21 and BACE1 is essential for BACE1’s ER export, and TMP21 enhances APP/BACE1 co-residency and might guide both APP and immature BACE1 in lipid rafts-like structures.In summary, this study defined the roles of TMP21 in AD pathogenesis. It demonstrated for the first time the genetic association between TMP21 and AD. The study also found that TMP21 facilitates APP amyloidogenic processing by modulating BACE1 maturation and trafficking, leading to increased BACE1 cleavage at Asp-1 site to generate Aβ. Therefore, interrupting the interaction between TMP21 and BACE1 to reduce Aβ production could be potential strategy to develop drugs for treating AD.
Alzheimer’s disease (AD) is the most common form of neurodegenerative diseases. Its neuropathology is characterized by extracellular amyloid plaque deposition, intracellular neuritic fibrillary tangles and neuronal loss. The extracellular amyloid plaque consists of amyloid β (Aβ) protein, which is derived from β- and γ- cleavage of amyloid precursor protein (APP). The abnormal accumulation of Aβ initiates neuronal dysfunction and plays an important role in AD pathogenesis.Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme that cleaves ubiquitin at its carboxyl terminal. Dysfunction of UCHL1 has been implicated in various neurodegenerative diseases including childhood-onset progressive neurodegeneration, Alzheimer’s disease and Parkinson’s disease. UCHL1 protein level is reduced in AD and is inversely proportional to the number of neurofibrillary tangles in AD brains.Overexpression of UCHL1 could rescue learning and memory deficits in AD mouse model. However, whether UCHL1 affects APP processing, Aβ production or AD pathogenesis remains unknown. This thesis entails a thorough examination of the role of UCHL1 in AD pathogenesis. First, UCHL1 gene transcriptional regulation was investigated. We identified a functional NF-κB binding site within its 5’promoter region. We found that NF-κB signaling down-regulated UCHL1 transcription. Next we demonstrated that UCHL1 affected APP processing and Aβ production by facilitating the degradation of APP, the precursor of Aβ, and BACE1, the β-secretase in vivo. The results were verified by transgene expression and pharmacological inhibition of UCHL1 in multiple cell lines. Moreover, we showed in neuroblastoma cell lines and primary neuronal culture that UCHL1 protected against oxidative stress- and Aβ-induced neuronal apoptosis by interfering with the caspase 8/caspase 3 pathway. Finally, we demonstrated that UCHL1 reduced Aβ production, inhibited amyloid plaque formation and rescued memory deficits in AD mouse models. In summary, this study investigated the effect of UCHL1 on AD pathogenesis. It demonstrated for the first time that UCHL1 delays the development of AD pathology by regulating APP processing and reducing Aβ production. Furthermore, our findings indicated that transgene expression of UCHL1 is a disease-modifying strategy for AD therapeutic design.
Pathogenic mutations in amyloid-β precursor protein (APP) and presenilins (PS) genes cause familial Alzheimer’s disease (FAD). FAD is an uncommon form ofAlzheimer’s disease (AD) with early onset (before age 65) and a rapid progressionbut its neuropathology is indistinguishable from the sporadic AD. Amyloid plaqueis the unique hallmark of AD, which consists primarily of 40- and 42-residueamyloid β protein (Aβ40 and Aβ42) with the more hydrophobic Aβ42 as its majorcomponent. Aβ is derived from APP through sequential cleavages by β-secretaseand γ-secretase. According to the “Amyloid hypothesis”, Aβ accumulationinitiates the pathogenic cascades leading to AD, including the formation ofneurofibrillary tangles, activation of astrocytes and neuronal loss. It has been wellestablished that pathogenic mutations in both APP and PS genes contribute to ADpathogenesis via impaired generation of Aβ. This powerful genetic discoverylends great credence to the “Amyloid hypothesis”, given that APP is the precursorof Aβ and PS acts as the enzyme to generate Aβ. The thorough understanding ofthe mechanism of these pathogenic mutations could lead to decipher the ADconundrum. Until now, all pathogenic APP mutations are autosomal dominantmutations except for APPA673V. We discovered that APPA673V structurallyfacilitates β-cleavage at Asp-1 site while inhibited the general APP processingincluding all α-/β-/γ-cleavages possibly due to the intensified lysosome-dependentdegradation. The overall effect of APPA673V on the production of Aβ makes thehomozygous state necessary for APPA673V to produce enough Aβ to initiate ADpathogenesis. Mutations in PS genes are another major cause of FAD. As anothersubstrate of γ-secretase apart from APP, Notch plays a fundamental role inneurodevelopment and neurodegeneration. It has been well established thatpathogenic PS mutations impaired Notch signaling. PS1ΔS169 is a recentlydiscovered PS1 mutation in a Chinese FAD family. We extensively characterizedthe function of PS1ΔS169 in mammalian cells and transgenic mice and found thatPS1ΔS169 promoted AD pathogenesis via altering γ-cleavage of APP withoutimpairing Notch processing, excluding the contribution of Notch signaling to ADpathogenesis. Our study highlights the possibility of developing specific γ-secretase inhibitors, which may spare Notch signaling in AD therapy.
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that plays a part in a number of physiological processes ranging from glycogen metabolism to gene transcription. Recent studies indicated that GSK3 also involved in the formation of Alzheimer’s disease (AD) pathologies: neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles develop when abnormal tau proteins accumulate inside neurons and form insoluble filaments, and amyloid plaques develop when the amyloid β protein (Aβ) accumulates in increasingly insoluble forms. The Aβ peptide is generated through sequential cleavages of the β-amyloid precursor protein by β-secretase (BACE1) and γ-secretase. Accumulation of insoluble Aβ is believed to trigger the initial series of neurodegenerative events leading to AD. Therefore, inhibition of the pathways that lead to Aβ generation will have therapeutic implications for AD treatment.The mechanism by which GSK3 affects APP processing and Aβ production has been controversial. Previous published reports have found differential effects on GSK3-mediated APP processing. This thesis entails a thorough investigation of GSK3’s role in APP processing and Aβ production. First, the therapeutic effects of the anti-convulsant drug, valproic acid (VPA) were tested in AD modeled mice. VPA, a known GSK3 inhibitor could interfere with Aβ production, and rescued memory deficits. In addition to inhibiting GSK3 activity, VPA also stimulate a plethora of signaling cascades. To further our understanding of GSK3’s effect on APP processing, a GSK3 specific pharmacological inhibitor (AR-A014418) and siRNA technologies were used in our systems. With specific GSK3β inhibition, we showed that BACE1-mediated cleavage of APP and Aβ production were reduced. Moreover, GSK3β induced BACE1 gene expression depends on NFκB activity. Additionally, specific inhibition of GSK3 also reduced Aβ production and neuritic plaque formation in AD modeled mice, as well as improved memory functions.Finally, this thesis examined in detail the role of GSK3 in AD pathogenesis. This study demonstrated for the first time that the GSK3β signaling pathway regulates BACE1 transcription and facilitates Aβ production. These findings reinforced the notion that specific GSK3 inhibition is a safe and effective approach for treating AD.
Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia. The two major neuropathological hallmarks of AD are the depositionof amyloid-b (Ab) protein in neuritic plaques and the formation of neuro brillary tangles. Ab is generated from a larger Ab recursor protein (APP) following sequential cleavage by b- and g-secretase. APP can also be cleaved in a non-amyloidogenicpathway following sequential cleavage by a- and g-secretase. In addition to the pathogenic processing of APP, the g-secretase complex also cleaves a protein called Notch, which is essential for embryonic development and may be involved in learningand memory. Transmembrane emp24-like trafficking protein 10 (TMP21) is a 21 kDa transmembraneprotein involved in vesicular trafficking. Ubiquitously expressed, particularly in the plasma membrane, endoplasmic reticulum, and Golgi, TMP is vital to development, and homozygous knockout mice are embryonic lethal. Recently, TMP21 was found to play a second, pivotal role as a regulatory member of theg-secretase complex involved in AD pathogenesis. Knockdown of TMP21 increased Ab production without affecting Notch cleavage, making it a seductive target forAD research (Chen et al., 2006).This thesis shows that, similar to other members of the g-secretase complex, TMP21 is also degraded by the ubiquitin-proteasome pathway, as treatment with proteasomal inhibitors increased TMP21 protein levels in both a time- and dose-dependent manner. Furthermore, overexpression of TMP21 shifted APP processingfrom the a-secretase to b-secretase pathway in cell culture, and b-secretase andTMP21 could coimmunoprecipitate. This suggests that TMP21 may not only a ffect AD pathogenesis through its modulatory role on g-secretase or its trafficking ofAPP (Vetrivel et al., 2007), but also through its influence on b-secretase, providing a novel enzymatic target for future study.Finally, this work presents the only in vivo study of the behavioural consequencesof TMP21 suppression. Motor function, anxiety, and learning and memory were examined using a comprehensive test battery. Mice heterozygous for TMP21 werefound to have slightly enhanced physical abilities, increased anxiety, and potential anxiety-augmented de ficits in hippocampal learning and memory. This data willprove vital when examining future work regarding TMP21 suppression in a mouse model of AD.
Master's Student Supervision (2010 - 2018)
Repeated mild traumatic brain injury (rmTBI) has been thought to result in cumulative damage to cells of the brain, but the molecular mechanisms are not known. We investigated the effect of rmTBI on cognition, behavior and hippocampal gene expression using microarray analysis. Mice applied with rmTBI for 25 successive days and tested at 1 week and 4 weeks after the injury respectively, showed transient neurological deficit, impaired weekly body weight growth rate (BWGR), changed behaviors in elevated plus maze and deficit in spatial memory in the Morris water maze compared with sham injury mice. Microarray analysis suggested several rmTBI-induced expression differences in intracellular signaling, apoptosis and cell cycle, angiogenesis, cellular architecture, inflammation, oxidative stress, metabolism and transcriptional regulation, and neuronal plasticity-related genes. This study highlights some of the potential mechanisms that may play an important role in the development of rmTBI-induced functional deficits. Further studies at different time points and in additional subregions of the brain are of interest in the search for molecular mechanisms behind rmTBI-induced neuronal pathogenesis after the injury.
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease among elderly people. The main symptoms of AD are memory loss and cognitive deficits. One of the hallmarks of AD is neuritic plaques in the brain. Amyloid β protein (Aβ), a peptide of 39–42 amino acids, forms the predominant component of plaques. Aβ is generated from amyloid-β precursor protein (APP) by sequential cleavages mediated by β-secretase and γ-secretase.Previous studies have shown that BACE1 can cleave APP at the ASP+¹ site or at the Glu+¹¹ site of Aβ domain. Cleavage at ASP+¹ is required for generating full length Aβ and increases in cleavage at ASP+¹ site has been considered as one of the major pathological pathways in AD cases. Swedish mutant APP, carrying double mutations (Lys⁵⁹⁵-Met⁵⁹⁶ to Asn⁵⁹⁵-Leu⁵⁹⁶) close to the ASP+¹ site in APP gene, causes early onset of familial AD. The Swedish mutation increases BACE1 cleavage at ASP+¹ site, resulting in significant increase of Aβ production. However, how BACE1 regulates APP processing at ASP+¹ and Glu+¹¹ remains elusive. Our preliminary studies indicated that majority of wild type APP is cleaved by BACE1 at Glu+¹¹ site, in contrast, Swedish mutation shifts the major cleavage site from Glu+¹¹ to ASP+¹ , resulting in significant increase of Aβ production under pathological condition. This work provides new insights in the pathological pathway of AD and suggests a major potential for the pharmaceutical development.
The macrophage migration inhibitory factor (MIF) is a 12kDa cytokine with pro-inflammatory properties. Initially characterized as a lymphocyte-secreted factor which inhibits macrophage migration in vitro, MIF has emerged as a multi-faceted cytokine involved in many processes, including cellular responses to ischemia/reperfusion injury in the heart. The main objective of this thesis was to determine whether human MIF expression is induced following cerebral ischemia, the underlying mechanism by which MIF expression is regulated under stroke conditions and its role therein. Previous studies have shown that MIF expression and release from cells is induced during hypoxia. However, the underlying mechanism is not clear. To examine whether the induction of MIF gene expression was mediated by its transcriptional upregulation, the human MIF gene promoter was cloned and a luciferase assay was used to determine the presence of a hypoxia responsive region in the human MIF promoter. The presence of a functional HIF-1α binding site was demonstrated using an electrophoretic mobility shift assay (EMSA). The results showed that upregulation of MIF gene expression under stroke is mediated by the effect of hypoxia on an HRE in MIF gene promoter. MIF has been shown to protect cells from ischemia and oxidative stress-induced cell death. To determine whether MIF has a similar protective effect on neurons, rat primary cortical neurons were cultured and subjected to either oxygen-glucose deprivation or treatment with hydrogen peroxide. MIF significantly reduced both OGD and H2O2-induced cell death. The expression of MIF in human brain has not been characterized. To determine whether the expression of MIF in human brain is altered following ischemia, brain sections from 10 stroke patients were immunostained with an antibody against MIF. Blood vessel endothelial cells in the peri-infarct region of ischemic brain displayed strong MIF immunoreactivity. Normal brain endothelium showed no MIF immunoreactivity. To understand the consequence of increased MIF expression by endothelial cells following stroke, the adhesion of human monocytes to human brain endothelial cells exposed to MIF was evaluated in vitro. MIF suppressed the monocyte adhesion to endothelial cells. The findings presented here are the first to suggest a role for MIF in cerebral ischemia.