Select polyphenols protect mitochondria against amyloid aggregates in Alzheimer and Parkinson diseases

Alzheimer and Parkinson diseases are age-related neurodegenerative disorders in which formation of amyloid aggregates by amyloid-beta (Abeta) and α-synuclein (αS) proteins, respectively, are recognised critical events that occur early in the disease process. These aggregates cause disruption of mitochondrial function in neurons, initiating a pathophysiological cascade leading to bio-energetic collapse and ultimately neuronal cell death. The detailed mechanisms are, however, largely unknown. In vitro studies in our laboratory aimed to, (i) investigate destabilisation of mitochondrial phospholipid membranes by these amyloid aggregates and, (ii) explore the protective effect of select polyphenolic compounds on mitochondria. Exposure of mitochondria, isolated from human neuroblastoma SH-SY5Y cells, to amyloid aggregates induced a strong and dose-dependent release of cytochrome c, reflecting damage to the outer and/or inner mitochondrial membranes. Importantly, targeting of aggregates to mitochondria was shown to be dependent upon cardiolipin, a mitochondria-specific phospholipid known to play a critical role in launching apoptosis. Moreover, the ability of amyloid aggregates to damage mitochondrial membranes was confirmed using a liposome permeabilisation assay. Finally, we found that the polyphenol compounds morin, rosmarinic acid, epigallocatechingallate and black tea extract were potent mito-protectants, and may thus delay the onset of neurodegenerative diseasespeer-reviewe

The potential role of dietary polyphenols in Parkinson’s disease

Cumulative evidence now suggests that the abnormal aggregation of the neuronal protein alpha-synuclein is critically involved in the pathogenesis of synucleinopathies, of which Parkinson’s disease (PD) is the most prevalent. Development of neuropathology appears to be linked to events that accelerate the rate of aggregation of alpha-synuclein from monomers, via soluble oligomeric intermediates, into amyloid fibrils. Although increasing data suggest that oligomeric aggregates, not amyloid fibrils, disrupt or permeabilise cellular membranes, the nature of the neurotoxic species and its precise molecular mechanism still remain largely unknown, hampering the development of an effective treatment for the disease. Currently, there is no approved therapeutic agent directed toward preventing alpha-synuclein aggregation and only symptomatic therapies are available with a limited time-frame of utility. Numerous studies have demonstrated the protective effects of dietary polyphenols against neuronal damage in PD. The aim of this review is to look at what research has been done so far to show that dietary polyphenolic compounds can effectively interfere with alpha-synuclein oligomerisation. Evidence in the role and mechanisms of diet-derived phenolic products may guide the design of novel therapeutic drugs that can block early stages of amyloid self-assembly in PD and related synucleinopathies.peer-reviewe

The Molecular Pathology of Prion Diseases

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a group of invariably fatal neurodegenerative disorders. Uniquely, they may present as sporadic, inherited, or infectious forms, all of which involve conversion of the normal cellular prion protein (PrPC) into a pathogenic likeness of itself (PrPSc). Formation of neurotoxic PrPSc and/or loss of the normal function of native PrPC result in activation of cellular pathways ultimately leading to neuronal death. Prion diseases can affect both humans and animals, with scrapie of sheep, bovine spongiform encephalopathy (BSE), and Creutzfeldt-Jakob disease being the most notable. This review is intended to provide an overview of the salient scientific discoveries in prion research, mainly from a molecular perspective. Further, some of the major outstanding questions in prion science are highlighted. Prion research is having a profound impact on modern medicine, and strategies for prevention and treatment of these disorders may also find application in the more common neurodegenerative diseases.peer-reviewe

A fruitful fly forward : the role of the fly in drug discovery for neurodegeneration

AD, Alzheimer’s disease; APP, amyloid precursor protein; BBB, blood brain barrier; GFP, green fluorescent protein; HTS, high-throughput screening; HD, Huntington’s disease; LB, Lewy bodies; PD, Parkinson’s disease; PolyQ, Polyglutamine; RNAi, RNA interference; SNCA, α-synuclein gene; UAS, Upstream Activating Sequence.peer-reviewe

An audit of the management of diabetic ketoacidosis at St Luke’s Hospital

Aim: To perform an audit of the protocol used in the management of patients with Diabetic Ketoacidosis, in St Lukes Hospital. Methods: Patients admitted with `Diabetes Ketoacidosis', between 14th August 2004 and 14th August 2005, were identified from the Admission book at the Accident and Emergency Department. Data obtained from patients' medical records were collected according to a preset proforma. The criteria assessed by this audit included parameter monitoring, investigations performed, the type and amount of intravenous fluids given, the insulin regime and potassium supplements used. Results: From a total of fifty six patients, forty seven files were traced, of which seventeen satisfied the criteria for Diabetic Ketoacidosis. Two were excluded and fifteen were analysed. In the population studied the mean age was 28 years with a male predominance of 60%. Ten patients suffered from Type 1 Diabetes whilst two patients had Type 2 Diabetes. Three other patients were newly diagnosed. Only one patient had all parameters checked according to protocol. In the majority of patients, fluids given in the first 22 hours, coincided with the amount of fluids stated in the protocol whilst 6/15 (40%) patients were administered the requested amount of insulin via infusion pump. With regards to potassium replacement, 13/15 (87%) patients were started on potassium supplements at a later stage. The factors influencing the total time for conversion to a fixed insulin regime and the duration of stay in hospital were also analysed. Conclusion: Deviations from the protocol were identified in parameter recording, the type of intravenous fluids given and the doses of insulin and potassium supplementation administered. New Diabetic Ketoacidosis guidelines have now been developed.peer-reviewe

Aspirin-induced apoptosis of yeast cells is associated with mitochondrial superoxide radical accumulation and NAD(P)H oxidation

In previous studies, we observed that aspirin, a promising cancer-preventive agent, induces apoptosis in mitochondrial manganese superoxide dismutase(MnSOD)-deficient Saccharomyces cerevisiae cells grown aerobically in ethanol medium. In this study, we show that aspirin-induced apoptosis is associated with a significant increase in mitochondrial and cytosolic O2 and oxidation of mitochondrial NAD(P)H. A concomitant rise in the level of cytosolic CuZn-SOD activity failed to compensate for mitochondrial MnSOD deficiency. However, an observed increase in activity of Escherichia coli FeSOD targeted to the mitochondrial matrix of the MnSOD-deficient yeast cells, markedly decreased aspirin-induced accumulation of mitochondrial O 2 , significantly increased the mitochondrial NAD(P)H level and rescued the apoptotic phenotype. Indeed, recombinant yeast cells expressing E. coli FeSOD behaved in a similar manner to the parent wild-type yeast cells with native mitochondrial MnSOD activity. Wild-type cells consistently showed a decrease in mitochondrial O 2 and an increase in mitochondrial NAD(P)H levels in the presence of aspirin in ethanol medium. In fact, in wild-type cells, our studies supported an antioxidant action of aspirin. Taken together, our results indicate that a pro-oxidant effect of aspirin occurring predominantly in cells with compromised mitochondrial redox balance may be enough to overcome antioxidant defences resulting in apoptosis, as observed in MnSOD-deficient yeast cells.peer-reviewe

The effects of socioeconomic determinants on hypertension in a cardiometabolic at-risk European country

Background. A relationship has been established between socioeconomic status and hypertension. The aim of this study was to determine the prevalence of hypertension and to explore the links between hypertension and socioeconomic factors in the adult population of Malta. Methods. A national representative cross-sectional health examination study was performed between 2014 and 2016. Sociodemographic and medical history data was gathered by validated questionnaires while blood pressure was measured. Prevalence rates of known hypertension, newly hypertension, and global hypertension were calculated. Associations between sociodemographic characteristics and hypertension were identified through logistic regression models. Results. Hypertension contributed to 30.12% (CI 95%: 28.71–31.57) of the study population, with a male preponderance. The majority was known hypertensive (73.59% CI 95%: 71.01–76.02), with only three-quarters on medication. Multivariant analyses showed that increasing age and body mass index, male gender, and living in Gozo, Western district, and Northern Harbour district were associated with having hypertension. Conclusion. Hypertension is a problem in Malta especially in the male population and with increasing age and body mass index. Education did not exhibit any associated risk for having hypertension, which is inconsistent with the literature, while habitat localities played a role in hypertension development.peer-reviewe

Diabetes, pre-diabetes and their risk factors in Malta : a study profile of national cross-sectional prevalence study

Type 2 diabetes mellitus constitutes a global epidemic and a major burden on health care systems across the world. Prevention of this disease is essential, and the development of effective prevention strategies requires validated information on the disease burden and the risk factors. Embarking on a nationally representative cross-sectional study is challenging and costly. Few countries undertake this process regularly, if at all. This paper sets out the evidence-based protocol of a recent cross-sectional study that was conducted in Malta. Data collection took place from November 2014 to January 2016. This study presents up-to-date national data on diabetes and its risk factors (such as obesity, smoking, physical activity and alcohol intake) that will soon be publicly available. This protocol was compiled so that the study can be replicated in other countries. The protocol contains step-by-step descriptions of the study design, including details on the population sampling, the permissions required and the validated measurement tools used.peer-reviewe

Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2–8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a “housekeeping” activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on in vivo studies that point toward disturbances in snRNP assembly and the consequential transcriptome abnormalities as the primary drivers of the progressive neuromuscular degeneration underpinning the disease. Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression

Reviews of: "SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer's-like neuropathology"

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