Thiruma V. Arumugam (Garrie)

Vascular cognitive impairment (VCI) is the second leading cause of dementia with limited treatment options, characterised by cerebral hypoperfusion-induced white matter rarefaction (WMR). Subcortical VCI is the most common form of VCI, but the underlying reasons for region susceptibility remain elusive. Recent studies employing the bilateral cortical artery stenosis (BCAS) method demonstrate that various inflammasomes regulate white matter injury and blood-brain barrier dysfunction but whether caspase-1 inhibition will be beneficial remains unclear. To address this, we performed BCAS on C57/BL6 mice to study the effects of Ac-YVAD-cmk, a caspase-1 inhibitor, on the subcortical and cortical regions. Cerebral blood flow (CBF), WMR, neuroinflammation and the expression of tight junction-related proteins associated with blood-brain barrier integrity were assessed 15 days post BCAS. We observed that Ac-YVAD-cmk restored CBF, attenuated BCAS-induced WMR and restored subcortical myelin expression. Within the subcortical region, BCAS activated the NLRP3/caspase-1/interleukin-1beta axis only within the subcortical region, which was attenuated by Ac-YVAD-cmk. Although we observed that BCAS induced significant increases in VCAM-1 expression in both brain regions that were attenuated with Ac-YVAD-cmk, only ZO-1 and occludin were observed to be significantly altered in the subcortical region. Here we show that caspase-1 may contribute to subcortical regional susceptibility in a mouse model of VCI. In addition, our results support further investigations into the potential of Ac-YVAD-cmk as a novel treatment strategy against …

Age-associated cerebral small vessel disease (CSVD) represents a clinically heterogenous condition, arising from diverse microvascular mechanisms. These lead to chronic cerebrovascular dysfunction and carry a substantial risk of subsequent stroke and vascular cognitive impairment in aging populations. Owing to advances in neuroimaging, in vivo visualization of cerebral vasculature abnormities and detection of CSVD, including lacunes, microinfarcts, microbleeds and white matter lesions, is now possible, but remains a resource-, skills- and time-intensive approach. As a result, there has been a recent proliferation of blood-based biomarker studies for CSVD aimed at developing accessible screening tools for early detection and risk stratification. However, a good understanding of the pathophysiological processes underpinning CSVD is needed to identify and assess clinically useful biomarkers. Here, we …

Vascular inflammation and fibrosis are hallmarks of hypertension and contribute to the development of cardiovascular disease and cognitive impairment. However, current anti-hypertensive drugs do not treat the underlying tissue damage, such as inflammation-associated fibrosis. Human amnion epithelial cells have several properties amenable for treating vascular pathology. This study tested the effect of amnion epithelial cells on vascular pathology and cognitive impairment during hypertension. Male C57Bl6 mice (8–12 weeks) were administered vehicle (saline; n = 58) or angiotensin II (0.7 mg/kg/d, n = 56) subcutaneously for 14 d. After surgery, a subset of mice were injected with 106 amnion epithelial cells intravenously. Angiotensin II infusion increased systolic blood pressure, aortic pulse wave velocity, accumulation of aortic leukocytes, and aortic mRNA expression of collagen subtypes compared to …

Physiological processes that govern the normal functioning of mammalian cells are regulated by a myriad of signalling pathways. Mammalian mitogen-activated protein (MAP) kinases constitute one of the major signalling arms and have been broadly classified into four groups that include extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, and ERK5. Each signalling cascade is governed by a wide array of external and cellular stimuli, which play a critical part in mammalian cells in the regulation of various key responses, such as mitogenic growth, differentiation, stress responses, as well as inflammation. This evolutionarily conserved MAP kinase signalling arm is also important for metabolic maintenance, which is tightly coordinated via complicated mechanisms that include the intricate interaction of scaffold proteins, recognition through cognate motifs, action of phosphatases, distinct subcellular localisation, and even post-translational modifications. Aberration in the signalling pathway itself or their regulation has been implicated in the disruption of metabolic homeostasis, which provides a pathophysiological foundation in the development of metabolic syndrome. Metabolic syndrome is an umbrella term that usually includes a group of closely associated metabolic diseases such as hyperglycaemia, hyperlipidaemia, and hypertension. These risk factors exacerbate the development of obesity, diabetes, atherosclerosis, cardiovascular diseases, and hepatic diseases, which have accounted for an …

Chronic cerebral hypoperfusion (CCH) is postulated to underlie multiple pathophysiological processes in vascular dementia (VaD), including extracellular matrix dysfunction. While several extracellular matrix proteins, namely cyclophilin A (CypA), extracellular matrix metalloproteinase inducer (EMMPRIN) and gelatinases (matrix metalloproteinases, MMP-2 and -9) have been investigated in acute stroke, their involvement in CCH and VaD remains unclear. In this study, CypA-EMMPRIN-gelatinase proteins were analysed in a clinical cohort of 36 aged, cognitively unimpaired subjects and 48 VaD patients, as well as in a bilateral carotid artery stenosis mouse model of CCH. Lower CypA and higher EMMPRIN levels were found in both VaD serum and CCH mouse brain. Furthermore, gelatinases were differentially altered in CCH mice and VaD patients, with significant MMP-2 increase in CCH brain and serum, whilst …

Intermittent fasting (IF) has been shown to reduce cardiovascular risk factors in both animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction. However, the underlying molecular mechanisms behind these effects remain unclear. To shed light on the molecular and cellular adaptations of the heart to IF, we conducted comprehensive system-wide analyses of the proteome, phosphoproteome, and transcriptome, followed by

BackgroundAlzheimer’s disease (AD) and vascular dementia (VaD) are two of the commonest causes of dementia in the elderly. Of the myriad biomolecules implicated in dementia pathogenesis, sphingolipids have attracted relatively scant research attention despite their known involvement in multiple pathophysiological processes. The potential utility of peripheral sphingolipids as biomarkers in dementia cohorts with high concomitance of cerebrovascular diseases is also unclear.MethodsUsing a lipidomics platform, we performed a case–control study of plasma sphingolipids in a prospectively assessed cohort of 526 participants (non-cognitively impaired, NCI = 93, cognitively impaired = 217, AD = 166, VaD = 50) using a lipidomics platform.ResultsDistinct patterns of sphingolipid alterations were found in AD and VaD, namely an upregulation of d18:1 species in AD compared to downregulation of d16:1 …

Multiple consensus statements have called for preclinical randomized controlled trials to improve translation in stroke research. We investigated the efficacy of an interleukin-17A neutralizing antibody in a multi-centre preclinical randomized controlled trial using a murine ischaemia reperfusion stroke model. Twelve-week-old male C57BL/6 mice were subjected to 45 min of transient middle cerebral artery occlusion in four centres. Mice were randomly assigned (1:1) to receive either an anti-interleukin-17A (500 µg) or isotype antibody (500 µg) intravenously 1 h after reperfusion. The primary endpoint was infarct volume measured by magnetic resonance imaging three days after transient middle cerebral artery occlusion. Secondary analysis included mortality, neurological score, neutrophil infiltration and the impact of the gut microbiome on treatment effects. Out of 136 mice, 109 mice were included in the …

Background and purpose Hypertension increases the risk for cognitive impairment and promotes vascular and renal inflammation. We tested if immune cell infiltration occurs in the brain during hypertension and if it is associated with cognitive impairment. Experimental approach Male C57Bl/6 mice were administered vehicle, angiotensin II (0.7 mg/kg/d S.C.) or aldosterone (0.72 mg/kg/d S.C.) via osmotic minipumps. A subset of mice also received hydralazine (50 mg/kg) in their drinking water after minipump implantation. We measured systolic blood pressure, markers of inflammation, working memory and transcriptomic changes in the brain. Key results Administration of angiotensin II or aldosterone increased blood pressure and promoted blood-brain barrier dysfunction, leukocyte accumulation and impairment of working memory in mice. When co-administered with angiotensin II, hydralazine prevented the …

Vascular dementia is the second most common form of dementia after Alzheimer’s disease. Chronic cerebral hypoperfusion is a key contributor to the development of vascular dementia. In this chapter, we describe the surgical procedures used for bilateral carotid artery stenosis (BCAS) surgery to induce chronic cerebral hypoperfusion. Mice that undergo BCAS surgery develop the hallmarks of vascular dementia including white matter lesions, neuroinflammation, and cognitive impairment. This technique may be used for studies of chronic cerebral hypoperfusion and vascular dementia in mice.

The proteasome is an evolutionary conserved protease that recognizes and degrades damaged and misfolded proteins via proteolysis. 1 The 26S proteasome consists of the 19S regulatory subunit and the core proteolytic enzyme, 20S proteasome. 2 The proteasome-dependent degradation of tagged, polyubiquitinated proteins is an essential cellular pathway that regulates a wide range of cellular processes, including cell cycle, apoptosis, oxidative stress, cell proliferation and activation of transcription factors such as NF-κB. 3 In contrast to the ubiquitously expressed constitutive proteasome, which is the crucial cellular protease containing the three catalytic subunits, β1, β2 and β5, the immunoproteasome is induced via de novo assembly upon stimulation of cells by Type I and Type II interferons. The incorporation of newly synthetized catalytic subunits, β1i/LMP2, β2i/MECL-1 and β5i/LMP7, is an essential cellular strategy to eliminate intracellular bacteria and viruses. 4 The immunoproteasome exhibits an altered proteolytic function that is required for optimal generation of epitopes for presentation on major histocompatibility complex Class I (MHC-I) molecules in infected cells. It was shown that immunoproteasomes transiently replace constitutive proteasomes during an anti-bacterial (Listeria monocytogenes) and anti-viral (lymphocytic choriomeningitis virus) immune response in the liver. 5 Apart from their function in the generation of a broad pool of MHC-I ligands and in triggering effective activation of cytotoxic T lymphocytes, immunoproteasomes appear to act as a pro-inflammatory factor that is involved in tissue inflammation and damage, as …

Vascular cognitive impairment (VCI) describes a wide spectrum of cognitive deficits related to cerebrovascular diseases. Although the loss of blood flow to cortical regions critically involved in cognitive processes must feature as the main driver of VCI, the underlying mechanisms and interactions with related disease processes remain to be fully elucidated. Recent clinical studies of cerebral blood flow measurements have supported the role of chronic cerebral hypoperfusion (CCH) as a major driver of the vascular pathology and clinical manifestations of VCI. Here we review the pathophysiological mechanisms as well as neuropathological changes of CCH. Potential interventional strategies for VCI are also reviewed. A deeper understanding of how CCH can lead to accumulation of VCI-associated pathology could potentially pave the way for early detection and development of disease-modifying therapies, thus …

Inflammation is a hallmark mechanism of ischemic stroke-induced brain injury. Recent studies have shown that an intracellular multimeric protein complex known as an inflammasome is a key factor for inducing an inflammatory response, and apoptotic and pyroptotic cell death in ischemic stroke. Inflammasome assembly leads to the activation of pro-inflammatory caspases, and the maturation and secretion of pro-inflammatory cytokines IL-1β and IL-18. While the role of inflammasomes in ischemic stroke-induced neuronal death, and microglial activation and cell death have been established, little is known about the role of inflammasomes in astrocytes under ischemic conditions. In this study, we investigated the expression and activation of inflammasome components in protoplasmic and fibrous astrocytes under ischemic conditions. We found that both protoplasmic and fibrous astrocytes expressed a differential …

Introduction: Vascular stiffening and inflammation are hallmarks of hypertension and contribute to the development of cardiovascular disease and cognitive impairment. Current treatments for hypertension may reduce blood pressure but do not target the associated pathological changes and end-organ damage. It is also inconclusive from clinical trials whether anti-hypertensive medication can improve cognitive impairment. Cell therapy has great therapeutic potential as unlike single pharmacological agents, cells can deliver multiple mediators which could more effectively target complex disease mechanisms. Human amnion epithelial cells (AECs) have many properties (eg. anti-inflammatory, anti-fibrotic, and immunologically inert) that make them attractive candidates for a cell-based therapy for vascular and brain pathology. Aim: To test the potential of AECs to treat vascular and brain pathology in angiotensin II …

Objective:Hypertension greatly increases the risk for cognitive impairment, and is associated with inflammation of the brain. However, it is unclear to what extent there is neuroinflammation during hypertension and whether this promotes cognitive impairment. This study aimed to quantify neuroinflammatory and cognitive changes caused by administration of angiotensin II, and determine whether this is blood pressure-dependent.Design and method:Male C57Bl/6 mice were administered vehicle (saline; n= 33) or angiotensin II (0.7 mg/kg/d, n= 34) for 14 d via an osmotic minipump. A subset of mice also received hydralazine hydrochloride (50 mg/kg; n= 38) in their drinking water for 14 d after minipump implantation. Systolic blood pressure (SBP) was measured using tail-cuff; inflammation was assessed using flow cytometry and RNA sequencing; and recognition memory was evaluated using the novel object …

Subsequent to the online publication, an error was identified in Fig. 2G, originating from an oversight during the assembly of Fig. 2. Immediate corrective actions have been taken to address this error.

BackgroundChronically dysregulated neuroinflammation has been implicated in neurodegenerative dementias, with separate studies reporting increased brain levels of inflammatory mediators and gliosis in Alzheimer’s disease (AD) as well as in Lewy body dementias (LBD). However, it is unclear whether the nature and extent of neuroinflammatory responses in LBD are comparable to those in AD. In this study, we performed head-to-head measurements of a panel of cytokines in the post-mortem neocortex of AD versus the two major clinical subtypes of LBD, namely, dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD).MethodsPost-mortem tissues from the mid-temporal cortex (Brodmann area 21) of a cohort of neuropathologically well-defined AD, PDD and DLB patients were processed and measured for a comprehensive range of cytokines (IL-1α, IL-1Ra, IL-8, IL-10, IL-12p70, IL-13, IFN-γ …

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16176. In addition to this …

Colorectal cancer (CRC) is the second leading cause of cancer deaths. Though chemotherapy is the main treatment option for advanced CRC, patients invariably acquire resistance to chemotherapeutic drugs and fail to respond to the therapy. Although understanding the mechanisms regulating chemoresistance has been a focus of intense research to manage this challenge, the pathways governing resistance to drugs are poorly understood. In this study, we provide evidence for the role of ubiquitin ligase NEDD4 in resistance developed against the most commonly used CRC chemotherapeutic drug 5-fluorouracil (5-FU). A marked reduction in NEDD4 protein abundance was observed in a panel of CRC cell lines and patient-derived xenograft samples that were resistant to 5-FU. Knockout of NEDD4 in CRC cells protected them from 5-FU-mediated apoptosis but not oxaliplatin or irinotecan. Furthermore, NEDD4 …

Intermittent fasting (IF) remains the most effective intervention to achieve robust anti-aging effects and attenuation of age-related diseases in various species. Epigenetic modifications mediate the biological effects of several environmental factors on gene expression; however, no information is available on the effects of IF on the epigenome. Here, we first found that IF for 3 months caused modulation of H3K9 trimethylation (H3K9me3) in the cerebellum, which in turn orchestrated a plethora of transcriptomic changes involved in robust metabolic switching processes commonly observed during IF. Second, a portion of both the epigenomic and transcriptomic modulations induced by IF was remarkably preserved for at least 3 months post-IF refeeding, indicating that memory of IF-induced epigenetic changes was maintained. Notably, though, we found that termination of IF resulted in a loss of H3K9me3 regulation of the …