At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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Free Radicals in the Physiological Control of Cell Function

Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

Alzheimer's Disease: Genes, Proteins, and Therapy

▪ Abstract The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-κB is through interactions with an inhibitor protein called IκB. Recent evidence confirms the existence of multiple forms of IκB that appear to regulate NF-κB by distinct mechanisms. NF-κB can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-κB to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of IκB. Exciting new research has elaborated several important and unexpected findings that...

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THE NF-κB AND IκB PROTEINS: New Discoveries and Insights

Sixteen years have passed since the description of the nuclear factor-кB (NF-кB) as a regulator of к light-chain gene expression in murine B lymphocytes (Sen & Baltimore, 1986a) During that time, over 4,000 publications have appeared, characterizing the family of Rel/NF-кB transcription factors involved in the control of a large number of normal and pathological cellular processes The physiological functions of NF-кB proteins include immunological and inflammatory responses, developmental processes, cellular growth and modulating effects on apoptosis In addition, these factors are activated in a number of diseases, including cancer, arthritis, acute and chronic inflammatory states, asthma, as well as neurodegenerative and heart diseases

Activators and target genes of Rel/NF-kappaB transcription factors.

Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in beta-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m(2); 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m(2); 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative beta-cell volume, frequency of beta-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative beta-cell volume was increased in obese versus lean nondiabetic cases (P = 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative beta-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of beta-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of beta-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that beta-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased beta-cell apoptosis. Since the major defect leading to a decrease in beta-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and beta-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.

https://diabetes.diabetesjournals.org/content/diabetes/52/1/102.full.pdf

β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes

Hydrogen peroxide mediates amyloid beta protein toxicity.

beta-Amyloid protein (A beta) is a member of a small group of proteins that accumulate as amyloid deposits in various tissues. It has recently been demonstrated that the toxicity of A beta toward some neural cells is caused by oxidative damage. Since all of the amyloid diseases are characterized by protein deposited in the antiparallel beta-sheet conformation, it was asked whether there is a common toxic mechanism. It is shown here that the protein components of other human amyloidoses, including amylin, calcitonin, and atrial natriuretic peptide, are all toxic to clonal and primary cells. The toxicity is mediated via a free radical pathway indistinguishable from that of A beta. Experiments with synthetic peptides suggest that it is the amphiphilic nature of the peptides generated by their beta structure rather than their beta structure per se that causes toxicity. These results tend to rule out the alternative that amyloid toxicity is exclusively mediated via specific cell surface receptors.

https://www.pnas.org/content/pnas/92/6/1989.full.pdf

Amyloid peptides are toxic via a common oxidative mechanism

Amyloid protein (Af3) isamemberofa smallgroupofproteins thataccumulate asamyloid deposits invarious tissues. Ithasrecently beendemonstrated thatthe toxicity ofAj3toward someneural cells iscaused byoxidative damage. Since alloftheamyloid diseases arecharacterized by protein deposited intheantiparallel 3-sheet conformation, it wasaskedwhether there isacommontoxic mechanism. Itis shownherethattheprotein components ofotherhuman amyloidoses, including amylin, calcitonin, andatrial natri- uretic peptide, arealltoxic toclonal andprimary cells. The toxicity ismediated viaafree radical pathway indistinguish- ablefromthatofAf3. Experiments withsynthetic peptides suggest thatitistheamphiphilic nature ofthepeptides gen- erated bytheir ,3structure rather thantheir ,3structure per sethatcausestoxicity. Theseresults tendtoruleoutthe alternative thatamyloid toxicity isexclusively mediated via specific cell surface receptors. f-Amyloid protein (A,B) hasbeenimplicated inthepathogen- esis ofAlzheimer disease (AD)bythefacts that mutations in its precursor protein leadtotheoverproduction ofA13(1-5) andthat A,Bisdirectly toxic tosometypes ofcells (6-8). In addition toAD there arenumerous other humandiseases that arecharacterized bythedeposition ofamyloid invarious tissues (9). Although these amyloids contain different pro- teins, all arecharacterized bytheantiparallel }3-sheet confor- mation oftheir major protein component (9). AsinAD,the tissues surrounding these amyloid deposits frequently showa toxic response. Since theprotein components share asecond- arystructure buthavenoobvious sequence homology, itis possible thattheyhavea commonmechanism forcellular toxicity that isnonspecificially linked totheir unique state of peptide conformation orassembly. Thealternative isthat the responsive cells allhaveunique receptors fortherespective peptides. Themechanism bywhichAP3 causes cell death isthebest understood ofthehumanamyloidoses. Although themolec- ulardetails arenotcompletely known, A,3causes increased H202accumulation incells, resulting infree radical-induced lipid peroxidation and,ultimately, cell death(10). Thesource ofH202isthought tobefromtheactivation ofanNADPH- linked oxidase similar tothatfoundinneutrophils, forA,3 toxicity isblocked byrelatively specific inhibitors ofthis enzyme(10). Thefollowing experiments address theissue of whether there isa commonmechanism oftoxicity thatis shared byother peptides associated withhumanamyloidoses andexamine howthese mechanisms relate totheir secondary andtertiary structure.

R. Lesley

Papers

Hydrogen peroxide mediates amyloid beta protein toxicity.

Amyloid peptides are toxic via a common oxidative mechanism

Amyloidpeptides aretoxicviaacommonoxidative mechanism