中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Neuroscience 細胞死：最近の知見

Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level.

https://hal.archives-ouvertes.fr/hal-01635507/document

Oxidative stress and the amyloid beta peptide in Alzheimer's disease.

Summary The β secretase, widely known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), initiates the production of the toxic amyloid β (Aβ) that plays a crucial early part in Alzheimer's disease pathogenesis. BACE1 is a prime therapeutic target for lowering cerebral Aβ concentrations in Alzheimer's disease, and clinical development of BACE1 inhibitors is being intensely pursued. Although BACE1 inhibitor drug development has proven challenging, several promising BACE1 inhibitors have recently entered human clinical trials. The safety and efficacy of these drugs are being tested at present in healthy individuals and patients with Alzheimer's disease, and will soon be tested in individuals with presymptomatic Alzheimer's disease. Although hopes are high that BACE1 inhibitors might be efficacious for the prevention or treatment of Alzheimer's disease, concerns have been raised about potential mechanism-based side-effects of these drugs. The potential of therapeutic BACE1 inhibition might prove to be a watershed in the treatment of Alzheimer's disease.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(13)70276-X.pdf

Targeting the β secretase BACE1 for Alzheimer's disease therapy

We isolated the postsynaptic density from human neocortex (hPSD) and identified 1,461 proteins. hPSD mutations cause 133 neurological and psychiatric diseases and were enriched in cognitive, affective and motor phenotypes underpinned by sets of genes. Strong protein sequence conservation in mammalian lineages, particularly in hub proteins, indicates conserved function and organization in primate and rodent models. The hPSD is an important structure for nervous system disease and behavior.

/pdf/characterization-of-the-proteome-diseases-and-evolution-of-2geqh08jvs.pdf

Characterization of the proteome, diseases and evolution of the human postsynaptic density

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the β-secretase enzyme required for the production of the neurotoxic β-amyloid (Aβ) peptide that is widely considered to have a crucial early role in the etiology of Alzheimer’s disease (AD). As a result, BACE1 has emerged as a prime drug target for reducing the levels of Aβ in the AD brain, and the development of BACE1 inhibitors as therapeutic agents is being vigorously pursued. It has proven difficult for the pharmaceutical industry to design BACE1 inhibitor drugs that pass the blood–brain barrier, however this challenge has recently been met and BACE1 inhibitors are now in human clinical trials to test for safety and efficacy in AD patients and individuals with pre-symptomatic AD. Initial results suggest that some of these BACE1 inhibitor drugs are well tolerated, although others have dropped out because of toxicity and it is still too early to know whether any will be effective for the prevention or treatment of AD. Additionally, based on newly identified BACE1 substrates and phenotypes of mice that lack BACE1, concerns have emerged about potential mechanism-based side effects of BACE1 inhibitor drugs with chronic administration. It is hoped that a therapeutic window can be achieved that balances safety and efficacy. This review summarizes the current state of progress in the development of BACE1 inhibitor drugs and the evaluation of their therapeutic potential for AD.

/pdf/bace1-inhibitor-drugs-in-clinical-trials-for-alzheimer-s-3kpmkwq55w.pdf

BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease

INTRODUCTION The biennial 2019 Don Ostrow Yellow Retreat (DOTYR) in Trieste, Italy is a meeting of about 100 international participants representing the small but dedicated group of researchers working towards a better understanding of both the positive and negative clinical functions of bilirubin (Fig. 1). This 2-day retreat was organized by the Italian Liver Foundation (FIF). The retreat was divided into five topic sessions that included basic, clinical, and translational science research (detailed information on the topics and presentation may be found online at https:// www.fegato.it/fondazione-italiana-fegato.html). In this commentary, we will be giving our impressions of the current state of the field of bilirubin research as well as thoughts of where it may be headed.

Commentary on the Don Ostrow Trieste Yellow Retreat 2019: a successful biennium, what next?

Introduction Glaucoma is the second leading cause of blindness worldwide and despite its prevalence, there are still many unanswered questions related to its pathogenesis. There is evidence that oxidative stress and inflammation play a major role in disease progression. Glaucoma patients from several studies showed altered gene expression in leukocytes, revealing the possibility of using peripheral biomarkers to diagnose or stage glaucoma. The fact that glaucoma is associated with gene expression changes in tissues distant from the retina underscores the possible involvement of systemic oxidative stress and inflammation as potential contributing or compounding factors in glaucoma. Methods We assembled a list of oxidative stress and inflammatory markers related to glaucoma based on a review of the literature. In addition, we utilized publicly available data sets of gene expression values collected from peripheral blood mononuclear cells and macrophages from two patient groups: those chronically infected by the hepatitis C virus and those who have cleared it. Activation of the innate immune response can render cells or tissues more responsive to a second delayed proinflammatory stimulus. Additional gene expression data from these cells after subsequent polyinosinic:polycytidylic acid treatment, used to elicit an acute inflammatory response, allowed for the investigation of the acute inflammatory response in these groups. We used fold-change comparison values between the two patient groups to identify genes of interest. Results A comparison analysis identified 17 glaucoma biomarkers that were differentially expressed in response to HCV-mediated inflammation. Of these 17, six had significant p-values in the baseline vs treated values. Expression data of these genes were compared between patients who had cleared the Hepatitis C virus versus those who had not and identified three genes of interest for further study. Discussion These results support our hypothesis that inflammation secondary to Hepatitis C virus infection affects the expression of glaucoma biomarker genes related to the antioxidant response and inflammation. In addition, they provide several potential targets for further research into understanding the relationship between innate responses to viral infection and inflammatory aspects of glaucoma and for potential use as a predictive biomarker or pharmacological intervention in glaucoma.

Analysis of Glaucoma Associated Genes in Response to Inflammation, an Examination of a Public Data Set Derived from Peripheral Blood from Patients with Hepatitis C

Recommended Citation Riordan, Sean M.; LePichon, Jean-Baptiste; Shapiro, Steven; Cowden, John; VillaGullen, Monica; Thielemans, Laurence; Villanueva Garcia, Dina; and Aguirre-Hernandez, Jesus, "Weighted Pathway Genetic Load Analysis of Hyperbilirubinemic Infants Indicates a Potential Genetic Component for Susceptibility to Bilirubin Neurotoxicity" (2019). Posters. 82. https://scholarlyexchange.childrensmercy.org/posters/82

/pdf/weighted-pathway-genetic-load-analysis-of-hyperbilirubinemic-3j61ka2zrf.pdf

Weighted Pathway Genetic Load Analysis of Hyperbilirubinemic Infants Indicates a Potential Genetic Component for Susceptibility to Bilirubin Neurotoxicity

/pdf/developing-technologically-advanced-research-in-low-and-5b7q6zq15e.pdf

Sean M. Riordan

Papers

Commentary on the Don Ostrow Trieste Yellow Retreat 2019: a successful biennium, what next?

Analysis of Glaucoma Associated Genes in Response to Inflammation, an Examination of a Public Data Set Derived from Peripheral Blood from Patients with Hepatitis C

Weighted Pathway Genetic Load Analysis of Hyperbilirubinemic Infants Indicates a Potential Genetic Component for Susceptibility to Bilirubin Neurotoxicity

Developing Technologically Advanced Research in Low- and Middle-Income Countries