May
25
May
19
Hot Off the Press: Cystathionine β-Synthase Inhibition Is a Potential Therapeutic Approach to Treatment of Ischemic Injury
Cystathionine β-synthase (CBS) is the central nervous system’s major producer of hydrogen sulfide (H2S), which has been reported to exacerbate stroke outcome in experimental models. This study led by Chan Su Jing and Peter Wong showed that when SH-SY5Y cells were transfected to overexpress CBS, the cells were able to synthesize H2S when exposed to high levels of enzyme substrates but not substrate concentrations that may reflect normal physiological conditions. At the same time, these cells demonstrated exacerbated cell death when subjected to oxygen and glucose deprivation (OGD) together with high substrate concentrations, indicating that H2S production has a detrimental effect on cell survival. This effect could be abolished by CBS inhibition. The same effect was observed with primary astrocytes exposed to OGD and high substrates or sodium hydrosulfide. In addition, CBS was upregulated and activated by truncation in primary astrocytes subjected to OGD. When rats were subjected to permanent middle cerebral artery occlusion, CBS activation was also observed. These results imply that in acute ischemic conditions, CBS is upregulated and activated by truncation causing an increased production of H2S, which exacerbate the ischemic injuries. Therefore, CBS inhibition may be a viable approach to stroke treatment.
Reference
Chan SJ, Chai C, Lim TW, Yamamoto M, Lo EH, Lai MK, Wong PT (This paper).
September
29
Hot Off the Press: Differential Alterations of Neocortical GluN Receptor Subunits in Patients with Mixed Subcortical Ischemic Vascular Dementia and Alzheimer’s Disease
Glutamatergic deficits are well-established neurochemical findings in Alzheimer’s disease (AD) and are thought to underlie both cognitive and behavioral symptoms of the disease. However, it is unclear whether subcortical ischemic vascular dementia (SIVD) and mixed SIVD/AD (MixD) manifest similar changes in the glutamatergic system. In this study, we measured the immunoreactivities of NMDA receptor GluN1, GluN2A, and GluN2B subunits in SIVD and MixD in postmortem neocortical tissues from a cohort of well-characterized, longitudinally followed-up patients with SIVD and MixD, together with age-matched controls. We found a significant reduction of GluN1 only in MixD, while significant increases of GluN2A and GluN2B were found only in SIVD. Furthermore, GluN1 loss and GluN2A/2B upregulation was associated respectively with higher Braak stages and lacunar infarct scores. Our data therefore suggest that the differential alterations of GluN subunits in SIVD and MixD may result from separate, interacting disease processes, and point to the potential utility of glutamatergic approaches for pharmacotherapy.
Reference
Mohamed NE, Lee JH, Francis PT, Esiri MM, Chen CP, Lai MK (This paper).
September
8
Believe Big…
August
22
Hot Off the Press: Autoantibodies to GM1 and GQ1bα are not Biological Markers of Alzheimer’s Disease
Uncovering novel biomarkers which lead to better diagnosis, prognosis and treatment is undoubtedly an important endeavor, but sometimes, finding what is not a biomarker may be worthwhile as well. Gangliosides are complex ceramide-glycosphingolipids known to play important roles in neuronal development. The GM1 ganglioside binds to β-amyloid and prevents β-sheet conformational changes (Yanagisawa et al., 1995), while GQ1bα and GT1aα are cholinergic neuron-specific gangliosides found to be increased in murine AD models (Ariga et al. 2010; Ariga et al. 2013a). Antibodies to gangliosides have been detected in AD, but the differences compared to controls were too low to be useful for diagnosis (Chapman et al. 1988). Other studies suffered from small patient numbers (n = 4, Hatzinfilippou et al. 2008), or low cut-off values resulting in low specificity (Ariga et al. 2013b).
In this study led by Prof. Nobuhiro Yuki, we measured serum levels of anti-ganglioside antibodies in patients with clinically diagnosed AD (n = 22) and vascular dementia (n = 14) and compared them to sera of patients with Guillain-Barré syndrome (GBS) and multifocal motor neuropathy (MMN), diseases where the antibodies are thought to be pathogenic; as well as to normal controls. We found that titers of IgG and IgM anti-GM1, anti-GQ1bα, and anti-GT1aα antibodies did not differ among AD, vascular dementia, and normal controls, and were remarkably lower than those in GBS and MMN. Our results suggest that the anti-ganglioside antibodies are unlikely to be pathogenic in AD or useful as biomarkers.
References
Miura Y, Miyaji K, Chai YL, Chen CL, Lai MK, Yuki N (This paper).
Ariga T, Yanagisawa M, Wakade C, Ando S, Buccafusco JJ, McDonald MP, Yu RK (2010) Ganglioside metabolism in a transgenic mouse model of Alzheimer’s disease: Expression of Chol-1α antigens in the brain. ASN Neuro 2: e00044.
Ariga T, ItokazuY, McDonald MP, Hirabayashi Y, Ando S, Yu RK (2013a) Brain gangliosides of a transgenic mouse model of Alzheimer’s disease with deficiency in GD3-synthase: Expression of elevated levels of a cholinergic-specific ganglioside, GT1aα. ASN Neuro 5: 141-148.
Ariga T, Kubota M, Nakane M, Oguro K, Yu RK, Ando S (2013b) Anti-Chol-1 antigen, GQ1bα, antibodies are associated with Alzheimer’s disease. PLoS One 8: e63326.
Chapman J, Sela BA, Wertman E, Michaelson DM (1988) Antibodies to ganglioside GM1 in patients with Alzheimer’s disease. Neurosci Lett 86: 235-240.
Hatzifilippou E, Koutsouraki E, Banaki T, Traka M, Costa VG, Baloyannis SJ (2008) Antibodies against GM1 in demented patients. Am J Alzheimers Dis Other Demen 23: 274-279.
Yanagisawa K, Odaka A, Suzuki N, Ihara Y (1995) GM1 ganglioside-bound amyloid beta-protein (Aβ): A possible form of preamyloid in Alzheimer’s disease. Nat Med 1: 1062-1066.
July
10
Welcome 2014 Honours Students!
From Left: Ferny Wong, Oh Wanling, Joey Lim and Atiqa Bte Zulkifli
June
24
Hot Off the Press: Andrographolide attenuates interleukin-1β-stimulated upregulation of chemokine CCL5 and glial fibrillary acidic protein in astrocytes
Andrographolide is a bioactive molecule isolated from Andrographis paniculata with anticancer and anti-inflammatory activities. In this study, we tested the effects of andrographolide on astrocyte-mediated neuroinflammatory responses. Cultured rat primary astrocytes were treated with proinflammatory cytokine interleukin 1β with or without pretreatment with andrographolide, and then processed for measurements of chemokine C-C motif ligand 5 (CCL5) and glial fibrillary acidic protein. The activation status of nuclear factor-κB activation that may underlie CCL5 upregulation was also measured. Andrographolide pretreatment was found to attenuate the upregulation of CCL5 and glial fibrillary basic protein as well as reduce the phosphorylation of nuclear factor-κB p65 and IκBα after interleukin 1β stimulation. These data suggest that andrographolide should be evaluated further as a therapeutic for central nervous system diseases characterized by astrocyte-mediated neuroinflammatory processes. 
Reference
Wong SY, Chan SJ, Wong WS, Wong PT, Lai MK (This paper).
May
6
Hot Off the Press: The brain lipidomes of subcortical ischemic vascular dementia and mixed dementia
Despite its importance as the leading cause of vascular dementia in Asia (Chen 2004), the primary pathogenic mechanisms in subcortical ischemic vascular dementia (SIVD) have remained elusive. Because of the lack of approved therapeutic agents for SIVD, there is a pressing need to identify novel therapeutic targets. In work led by collaborators Guanghou Shui and Markus Wenk, we performed comparative lipidomic analyses of SIVD and mixed dementia (i.e., SIVD and Alzheimer’s disease, MixD) which may confer new insights pertaining to the possible interaction between neurodegenerative and vascular mechanisms in the pathogenesis of dementia. Liquid chromatography coupled to mass spectrometry was used to comprehensively analyze the lipidomes of white and gray matter from the temporal cortex of nondemented controls, SIVD, and MixD subjects. Detailed molecular profiles highlighted the pathologic relevance of gray matter sphingolipid fatty acyl chain heterogeneity in dementia. In addition, the levels of sulfatides and lysobisphosphatidic acids were progressively increased in the temporal cortex gray matter from control to SIVD to MixD. White matter phospholipid profiles indicated possible adaptive mechanisms (i.e., increased unsaturation) to chronic ischemia in SIVD and elevated membrane degradation in MixD.
References
Chen CP (2004) Transcultural expression of subcortical vascular disease. J Neurol Sci 226:45-47.
Lam SM, Wang Y, Duan X, Wenk MR, Kalaria RN, Chen CP, Lai MK, Shui G (This paper).
February
11
Hot Off the Press: Novel pathophysiological markers are revealed by iTRAQ-based quantitative clinical proteomics approach in vascular dementia
In research led by collaborator Newman Sze, we used an iTRAQ-2D-LC-MS/MS strategy for quantitative analysis of pooled lysates from the neocortex of 21 pathologically confirmed cases of vascular dementia (VaD) and matched non-neurological controls. A total of 144 differentially perturbed proteins out of 2284 confidently identified proteins (false discovery rate=0.3%) were shortlisted for bioinformatics analysis. Western blot analysis of selected proteins using samples from individual patients (n=10 per group) showed significant increases in the abundance of SOD1 and NCAM and reduced ATP5A in VaD. This suggests a state of hypometabolism and vascular insufficiency along with an inflammatory condition during VaD. Elevation of SOD1 and increasing trend for iron-storage proteins (FTL, FTH1) may be indicative of an oxidative imbalance that is accompanied by an aberrant iron metabolism. The synaptic proteins did not exhibit a generalized decrease in abundance (e.g. syntaxin) in the VaD subjects. This reported proteome offers a reference data set for future basic or translational studies on VaD.
Reference
Datta A, Qian J, Chong R, Kalaria RN, Francis P, Lai MK, Chen CP, Sze SK. (This paper).
November
14
Hot Off the Press: Decreased rabphilin 3A immunoreactivity in Alzheimer’s Disease is associated with Aβ burden
Synaptic dysfunction, together with neuritic plaques, neurofibrillary tangles and cholinergic neuron loss is an established finding in the Alzheimer’s disease (AD) neocortex. The synaptopathology of AD is known to involve both pre- and postsynaptic components. However, the status of rabphilin 3A (RPH3A), which interacts with the SNARE complex and regulates synaptic vesicle exocytosis and Ca2+-triggered neurotransmitter release, is at present unclear. In this study, we measured RPH3A and its ligand rab3A as well as several SNARE proteins in postmortem neocortex of patients with AD, and found specific reductions of RPH3A immunoreactivity compared with aged controls. RPH3A loss correlated with dementia severity, cholinergic deafferentation, and increased β-amyloid (Aβ) concentrations. Furthermore, RPH3A expression is selectively downregulated in cultured neurons treated with Aβ peptides. Our data suggest that presynaptic SNARE dysfunction forms part of the synaptopathology of AD.
Reference
Tan MG, Lee C, Lee JH, Francis PT, Williams RJ, Ramírez MJ, Chen CP, Wong PT, Lai MK (This paper).