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Science, Technology and Medicine open access publisher.Publish, read and share novel research. Protein misfolding and aggregation as the common molecular pathogenesis of neurodegenerative diseases.
2008 The pyridoxamine action on Amadori compounds: A reexamination of its scavenging capacity and chelating effect. 2000 Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of b-sheets in Alzheimer’s b-amyloid fibrils. 2004 Aging-related increase in oxidative stress correlates with developmental pattern of betasecretase activity and beta-amyloid plaque formation in transgenic Tg2576 mice with Alzheimer-like pathology. 2011 Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. 2006 Glycogen synthase kinase 3? and Alzheimer’s disease: pathophysiological and therapeutic significance. 2002 Supramolecular structure in full-length Alzheimer’s b-amyloid fibrils: evidence for a parallel b-sheet organizatioin from solid-state nuclear magnetic resonance. Key words: chromosome mapping, chromosomes, genetic markers, genetic linkage, major histocompatibility complex, multiple sclerosis, pedigree. This material is based upon work supported by the National Multiple Sclerosis Society, the National Institute of Health, and the Nancy Davis and Sandler Foundations. On February 15, 2001, the International Human Genome Sequencing Consortium and the private company Celera simultaneously reported the completion of the first draft of the human genome sequence (1,2).
The potential of genetic mapping for gene identification in complex diseases was highlighted in a study of type 2 diabetes (15). Genetic studies in MS in the previous decade were influenced by three large multistage whole genome screens performed in multiple-affected families ascertained in the United States, United Kingdom, and Canada (18-20). Although further work is necessary to better define the complete roster of MS loci, these studies represent real progress in mapping the full set of MS-associated genes. The HLA-DR2 haplotype (DRB1*1501 DQB1*0602) within the major histocompatibility complex (MHC) on chromosome 6 is the strongest genetic effect identified in MS and has consistently demonstrated both linkage and association in family and case-control studies (28,29). The mechanism(s) underlying the genetic association of HLA-DRB1*1501-DQA1*0102-DQB1*0602 with MS are not yet fully understood. As summarized above, the MHC locus has consistently demonstrated both association and linkage with MS in case-control and family studies; however, the role of a gene within this region in determining clinical features or subtypes of MS is unclear. During the process of lesion formation, lymphocyte activation and recruitment, extravasation, and effector functions involve several cellular phenotypic changes triggered by the pathways of specific gene expression.
Genes play a primary role in determining who is at risk for developing MS, how the disease progresses, and how someone responds to therapy. This work was supported by the National Multiple Sclerosis Society, the National Institute of Health, and the Nancy Davis and Sandler Foundations. 13.Barcellos LF, Oksenberg JR, Green AJ, ME Garcia, Bucher P, Lincoln R, Rimmler JB, Pericak-Vance MA, Haines JL, Hauser SL. 43.University of California at San Francisco, Multiple Sclerosis Genetics Group, Research papers on multiple sclerosis candidate genes. 46.Schrijver HM, Crusius JB, Uitdehaag BM, Garcia Gonzalez A, Kostense PJ, Polman CH, et al.
Department of Molecular Microbiology & Immunology - Saint Louis University School of Medicine - H.
Research in my laboratory centers around investigations into the molecular mechanisms of aging. We are testing the above scenario by studies of transgenic mouse models for mitochondrial based disease. Surprisingly, our studies so far suggest that whatever the molecular mechanism is, it does not appear to involve a decline in the ability of the mitochondria to generate ATP.
Bensch KG, Mott JL, Chang SW, Hansen PA, Moxley MA, Chambers KT, de Graaf W, Zassenhaus HP, Corbett JA. Mott JL, Zhang D, Freeman JC, Mikolajczak P, Chang SW, Zassenhaus HP, Cardiac disease due to random mitochondrial DNA mutations is prevented by cyclosporin A.
Some genetic mutations responsible of neurodegenerative diseases render the causative proteins prone to misfold and to form beta-sheet-rich oligomers and amyloid fibrillar aggregates, resulting in their accumulation in the affected neurons and eventually leading to degeneration in the brain. LAN5 untreated (control), treated with rAb42 oligomers oligomers), and rAb42 oligomers and insulin (oligomers+insulin) were incubated with Mito Red and Hoechst 33258.
San Biagio2[1] Istituto di Biomedicina e Immunologia Molecolare (IBIM) – CNR, Italy[2] Istituto di Biofisica (Palermo unit) – CNR, Italy1. The genetic component of MS etiology is believed to result from the action of several genes of moderate effect.
This landmark effort resulted in an extraordinary amount of fundamental information and the promise of advancing our understanding of the underlying genetic basis of complex multifactorial diseases. The investigators followed original linkage data that implicated the distal long arm of chromosome 2 and identified a disease-associated intronic polymorphism in calpain-10, a ubiquitously expressed member of the calpain-like family of cysteine proteases. A fourth study concentrated on a genetically isolated region of Finland but was based on a small number of families (21). The next step is to systematically explore the degree of variability, primarily in coding but also in regulatory and intronic regions, in genes mapped to the candidate regions for direct association with disease (Figure 5). Key to the success of the proposed studies will be the availability of rapid reliable nonlabor-intensive methods for high-throughput polymorphism screening.
These MHC molecules may fail to negatively select (delete) autoreactive T cells within the embryonic thymic microenvironment. HLA-DR2 has been reported to be associated with lower age at onset, gender, severe, relapsing-remitting, and mild MS courses, or to have no influence (34-40). Cytokines, adhesion molecules, growth factors, and other molecules (such as free radicals, proteases, and vasoactive amines) induce and regulate numerous critical cell functions. With the aid of high-capacity technologies, the combined analysis of genomic and transcriptional information, together with the modeling of genetic networks, will define a useful conceptual model of pathogenesis.
Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatibility complex.
A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22.
Clustering of nonmajor histocompatibility complex susceptibility candidate loci in human autoimmune diseases.
HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation. Expression and crystallization of the complex of HLA-DR2 (DRA, DRB1*1501) and an immunodominant peptide of human myelin basic protein.
Crystal structure of HLA-DR2 (DRA*0101, DRB1*1501) complexed with a peptide from human myelin basic protein.
Structural features of autoreactive TCR that determine the degree of degeneracy in peptide recognition. Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis. Western versus Asian types of multiple sclerosis: immunogenetically and clinically distinct disorders.
A study of the HLA-DR region in clinical subgroups of multiple sclerosis and its influence on prognosis. Major histocompatibility complex class II alleles and the course and outcome of MS: a population-based study.
Identification of genetic loci controlling the characteristics and severity of brain and spinal cord lesions in experimental allergic encephalomyelitis. Association of interleukin-1beta and interleukin-1 receptor antagonist genes with disease severity in MS.
Relevance of interleukin 1 receptor antagonist intron 2 polymorphism in Italian MS patients. Genetic variation in the tumor necrosis factor alpha gene and the outcome of multiple sclerosis.
Transcriptional analysis of multiple sclerosis brain lesions reveals a complex pattern of cytokine expression. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease.
Reveal, a general reverse engineering algorithm for inference of genetic network architectures. Individuals with the variant may be up to 3 to 5 times more likely to develop Late Onset Alzheimer’s disease (LOAD). Recent and ongoing research indicates that polyphenols present in berries and other fruits and vegetables provide protective and supportive nourishment to critical structures (i.e. A recent study of nearly 12,000 Swedish twin pairs, age 65 and older, determined that 58% to 79% of Alzheimer’s risk is genetic. Damaged neurons were considered damaged goods, never to regain their function, and without any hope for regeneration.
A cluster of signs that define Mild Cognitive Impairment (MCI), especially memory loss and forgetfulness, may be the early warning indicators that you are at risk for developing AD. ALA is a unique antioxidant in that it is both water and fat-soluble, which enables ALA to confer its antioxidant benefits to all the cells and cell structures of the body.
It is most often associated with cancer treatments and there are various types and of immunotherapy that either stimulate or suppress immune responses.Of late, there has been a surge of research exploring the application and effectiveness of immunotherapy in Alzheimer’s disease.
One of the major ideas about the cause of aging postulates that mitochondria slowly lose their capacity to generate energy as individuals age.
The right heart was removed from a 6 month old transgenic mouse; the one on the left is from a same aged control littermate. We have created a transgenic mouse, which rapidly accumulates mutations only in the mitochondrial DNA of the heart. Selective mtDNA mutation accumulation results in beta-cell apoptosis and diabetes development.
Mitochondrial DNA mutations may contribute to aging via cell death caused by peptides that induce cytochrome c release. A transgenic model to study the pathogenesis of somatic mtDNA mutation accumulation in beta-cells. Mitochondrial DNA mutations cause resistance to opening of the permeability transition pore. Gene expression profile in dilated cardiomyopathy caused by elevated frequencies of mitochondrial DNA mutations in the mouse heart.
Purification and characterization of an RNA dodecamer sequence binding protein from mitochondria of Saccharomyces cerevisiae.
This mechanism is retained common to a broad variety of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington disease, Amyothophic Lateral Sclerosis and Frontotemporal Lobar degeneration. IntroductionProtein aggregation is a very fascinating matter due to its implication in many human neurodegenerative diseases and its relevance in food and pharmaceutical industries. This mechanism is retained common to a broad variety of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington disease, Amyothophic Lateral Sclerosis and Frontotemporal Lobar degeneration.Type 2 diabetes (T2D) is classified as a metabolism disorder and it is often associated with microvascular and macrovascular complications, including retinopathy, nephropathy, neuropathy and cardiovascular disease. The incomplete penetrance of MS susceptibility alleles probably reflects interactions with other genes, posttranscriptional regulatory mechanisms, and significant environmental influences. A complex trait is defined by a genetic component that is not strictly Mendelian (dominant, recessive, or sex-linked) and involves the interaction, either programmed or stochastic, of two or more genes. Single-nucleotide polymorphisms (SNPs) are the most frequently found DNA sequence variation in the human genome (on average 1 per 1,000 or 2,000 bases).
In all likelihood, the use of phenotypic (clinical and paraclinical), epidemiological, and demographic variables will assume increasing importance as stratifying elements so as to address the fundamental question of genotype-phenotype correlation in autoimmune demyelination. These cells can then become activated by a second stimulatory signal and initiate an immune response. In the EAE disease model, MHC genes appear to influence primarily susceptibility and penetrance, whereas other loci modulate specific phenotypes, such as location in brain or spinal cord, demyelination, and severity of inflammation (41,42). The combination will also determine a framework for understanding the mechanisms of action of existing therapies for this disorder, as well as the rationale for novel curative strategies. This study showed that in male identical twins, when one brother had Alzheimer’s disease, the other developed the disease 45% of the time. Fortunately, for those concerned about recovery from brain trauma, stroke, and the neurological damage associated with Alzheimer’s disease (AD), there is promising research indicating that growth factors in the brain, not only promote brain structure and function associated with memory and learning, they can promote brain growth and recovery from damaging events to the brain. Another important characteristic of ALA is that it is part of the antioxidant team that includes vitamin E, C, coenzyme Q10 and glutathione. This insulin resistance pattern which defines the disease process of the above mentioned disorders, is now seen as a link to the degenerative spiral that occurs in Alzheimer’s disease (AD) over and above the role of insulin in glucose metabolism in the brain. However, severe side effects that include brain bleeding has hindered progress in the field. I am also extremely interested in warding off a family history of Alzheimer’s and Dementia. It is known that the frequency of mitochondrial DNA mutations rises exponentially with aging. Our current hypothesis is that the mutations lead to a dysregulation of the mitochondrial permeability transition pore which is intimately linked to the regulation of apoptosis and, thus, cell survival. Mitochondrial activity is indicated by red arrows, fragmentation of nuclei is indcate by blu arrows. In some cases, the aggregation of protein is a natural phenomenon occurring in living organisms.
A diabetes affected person has an elevated quantity of glucose in the blood (hyperglycemia) that is caused by the inability of the body either to produce any insulin or enough insulin, or by the inability of the cells to respond properly to the insulin producted in the pancreas. Mitochondrial activity is indicated by red arrows, fragmentation of nuclei is indcate by blu arrows.Moreover, unpublished results indicate that insulin counteracts oxidative stress induced by amyloid beta by activation of Akt survival pathway. Equally significant is that genetic heterogeneity also likely exists, meaning that specific genes influence susceptibility and pathogenesis in some affecteds but not in others. This category clusters most of the common diseases in children (birth defects, mental retardation) and in adults (cancer, cardiovascular diseases, and autoimmunity, including multiple sclerosis (MS)). The studies identified about 60 genomic regions with a potential involvement in MS, but total or even predominant overlapping between the different screens was absent. SNPs are thought to represent old and stable mutations evenly distributed throughout the entire genome. These studies will be linked necessarily to the development of novel mathematical formulations designed to identify modest genetic effects, as well as interactions between multiple genes, and interactions between genetic, clinical, and environmental factors. In addition, MHC molecules present on stromal cells on the thymus during development help determine the specificity of the mature T cell repertoire. The HLA-DRa0101-DRb1501 heterodimer binds with high affinity to the myelin basic protein (MBP) 89-55 peptide. By analogy, it will be of interest to identify which loci are involved in the initial pathogenic events or influence the development and progression of the disease.
The field of functional genomics involves the use of high-throughput methods to analyze the expression of hundreds or thousands of genes simultaneously. In female identical twins, when one sister had Alzheimer’s disease, the other developed the disease 60% of the time.


ALA regenerates theses antioxidants as they are metabolized in their protective antioxidative roles. Insulin resistance and its role in inflammation, and impaired insulin function in the brain are now understood to be underlying pieces of the Alzheimer’s puzzle. Increased inflammatory responses when immunotherapy is designed to target amyloid beta deposition (amyloid beta immunotherapy) is another of the conundrums researchers have encountered. Medicine can be so very powerful when we are able to identify the biochemical inefficiencies, apply specific dietary and nutritional remedies and compile a protocol to heal not just an individual, but generations. It has also been shown that in many tissues mitochondrial respiratory capacity declines with age. These mice develop cardiac disease early in life, which often is manifested as congestive heart failure. Perturbations in the function of that pore are hypothesized to communicate to the nucleus via signal transduction pathways involving nuclear receptor – possibly the peroxisome-proliferator activated receptors.
Akt traslocates from the cytoplasm to nucleus where phophorylates FOXO3a that, in turn, moves from the nucleus to the cytoplasm inhibiting, in this way the transcription of the FOXO-dependent genes. Some loci may be involved in the initial pathogenic events, while others could influence the development and progression of the disease. The human MHC (the Human Leukocyte Antigen (HLA) system) consists of linked gene clusters located on the short arm of chromosome 6 at 6p21.3, spanning almost 4 million base pairs.
X-ray crystallography of the DR-MBP peptide complex reveals a DRb1501 structure different from other DRb molecules in that aromatic residues are preferred in the P4 pocket of the peptide binding domain (Figure 6) (31,32).
Here, genes that are logical possibilities to play a role in a disease (candidate genes) are considered; for MS, candidate genes might encode cytokines, immune-receptors, myelin components, and proteins involved in viral clearance (43). These large-scale explorations of gene expression have become virtually routine over the past few years. While this study did not delve into specific gene influences in LOAD, numerous studies have identified Apolipoprotein E4 (ApoE4), as a prominent genetic risk factor for LOAD. The decrease in ATP synthesis compromises cellular physiological function leaving the cell vulnerable to stress and less able to repair damage -culminating in senescence. At the time this mouse developed severe heart failure, its cardiac mitochondria had a frequency of mitochondrial DNA mutations that would normally be found in an 80-year-old person.
So, even though the blood has plenty of glucose, the cells are incapable of getting it for their essential energy and growth requirements. Since after Abeta-induced oxidative stress are usually activated pro-apoptotic genes, their trascriptional inhibition helps the survival program (Picone et al., 2011). The past few years have seen significant progress in the developments of laboratory and analytical approaches to study non-Mendelian complex genetic disorders and to define the pathological basis of demyelination.
It is also possible that the study design in each case underestimated the confounding influence of disease heterogeneity and the limitations of parametric methods of statistical analysis. Many of the HLA genes are highly polymorphic, resulting in the generation of enormously diverse numbers of different genotypic combinations or haplotypes.
Several studies examining the influence of such group of genes (IL-1R, TNF, APOE, CTLA4, and CCR5 among others) on disease course and severity in MS have been reported and await confirmation (44-49). However, the statistical and mathematical treatment of the extraordinary large resulting data sets is largely an emerging discipline (52,53). About 25% of the population has one copy of the ApoE4 gene and individuals with the the ApoE4 gene are estimated to make up approximately 40%-80% of the Alzheimer’s disease population.
One major source of that stress derives from the mitochondria itself ' namely reactive oxygen species that are natural byproducts of respiration. Mitochondrial DNA mutations activate the mitochondrial apoptotic pathway and cause dilated cardiomyopathy. There are three main types of diabetes: Type 1 diabetes (T1D) (referred to as insulin-dependent diabetes and juvenile diabetes), results from the body's failure to produce insulin, and presently requires the person to inject insulin.
Moreover, it has been suggested that since insulin signalling in the brain is known to decline with age, the outcome of the balance of different molecules, as Akt and FOXO, represents a risk factor for AD that is well suited for therapeutic intervention. These developments have set the stage for the final characterization of the genes involved in MS susceptibility and pathogenesis. It should be noted, however, that because each study used a somewhat overlapping but different set of genetic markers and different clinical inclusion criteria, the direct comparison of results is not straightforward. The polymorphic residues that define an HLA allele are clustered in the antigen-peptide-binding groove of the molecule. The structural analysis also revealed that only two primary TCR contact residues of MBP p85-99 had to be conserved to properly stimulate antigen-specific clones (33). The careful and methodic mining of expression data could lead to the identification of coregulated genes and characterization of networks that underlie specific cellular process.
It is thought that the age-related increase in mtDNA mutations results in higher levels of oxidative stress which, in turn, not only causes damage to proteins and other cellular macromolecules, but also, in a Catch 22, leads to further elevations in the levels of mtDNA mutations. As mutation frequencies rise, their hearts dilate in order to maintain cardiac performance Figure 2. Type 2 diabetes (referred to as non-insulin-dependent diabetes mellitus, and adult-onset diabetes.) is associated with a reduced ability of insulin to stimulate glucose utilization (insulin resistance) and sometimes it is combined with an absolute insulin deficiency.
By restoring the balance of molecules to favour neuron survival, new drugs, designed to specifically enhance CNS insulin signalling, would provide a new and potentially significant class of AD therapeutics.9. The identification and characterization of the genes are likely to define the basic etiology of the disease, improve risk assessment, and influence therapeutics. Hence, the ability of an individual to respond to an antigen, whether foreign or self, and the nature of that response are largely determined by the unique amino acid sequences of HLA alleles. The data suggest that microbial peptides with only limited sequence identity with a self-peptide may activate autoreactive T cells. This complex organization is what ultimately defines the function and, therefore, the phenotype. View on Facebook·ShareThe Alzheimer's Solution 2 days ago In a placebo-controlled, double blind study that included patients with mild to moderate Alzheimer’s disease (AD), a pharmaceutical and synthetic Resveratrol stabilized levels of amyloid beta40 (Abeta40). This viscous circle ultimately culminates in either cell death or the vulnerability to late-onset diseases like Alzheimer's, Parkinson's, and Type II Diabetes. The third type, gestational diabetes, is when pregnant women, who have never had diabetes before, have a high blood glucose level during pregnancy and it may precede development of T2D. ConclusionsThe present chapter highlights the overlap and the many points of intersection existing between T2D and AD. This observation provided the rationale for focusing on associations between HLA genotypes and susceptibility to autoimmune disease (30).
Mathematical models of gene interaction in a rational scenario of network operation can now be tested, and accordingly, new hypotheses can be generated. We are characterizing these transgenic mice at the molecular level to discover how the rising frequency of mitochondrial DNA mutations leads to heart disease. Insulin resistence in the CNS results in the dysregulation of multiple extracellular and intracellular signaling cascades and molecular mechanisms, which in turn could lead to decrease in neuronal and synaptic functions up to neurodegeneration.
Emerging advances in protein analysis (mass spectroscopy, NMR (nuclear magnetic resonance) spectroscopy, X-ray crystallography, yeast two- or three-hybrid systems) (54) will facilitate the transition from gene identification to gene function.
Diabetes is increasing and the World Health Organization estimates that there will be a doubling of cases by 2025, largely as a result of lack of physical activity and poor dietary habits, both of which are risk factors for the disease. An understanding of how each molecular pathway intersects and affects the others is essential for the development of future drug intervention strategies for these pathologies.10.
Obesity, hypertension, hyper-cholesterolemia and hyperlipidemia are all associated with T2D (MedScape).Alzheimer’s disease (AD) is the most common form of dementia in the elderly. AcknowledgementsThe present work was supported by a Grant from the Italian Ministry of Universty and Scientific Research for Programs of Relevant National Interest (PRIN 2008 - prot. It is characterized by neuronal cell loss and increasing accumulation of neurofibrillary tangles (NTF) in neurons and amyloid fibers in neuritic plaques and in the walls of blood vessels (Wisniewski et al., 1997).
Amyloid beta-peptides of varying length (39–43 residues) are produced by cleavage of a transmembrane protein, the amyloid beta-protein precursor (APP) (Wilquet & De Strooper, 2004). Abeta42 has a much greater neurotoxity than Abeta40 and its aggregation kinetics is faster than other beta-petides (Davis & Van Nostrand, 1996). View on Facebook·ShareThe Alzheimer's Solution 6 days ago Several studies have shown that a decreased sense of smell is linked to the onset of Alzheimer’s and other neurodegenerative diseases.
The loss of of the sense of smell (Anosmia) is correlated to the early stages (amnestic-MCI)) of late-onset Alzheimer’s disease (LOAD).
Evidence for a site-specific endonuclease in yeast mitochondria which recognizes the sequence 5'GCCGGC. This incurable, degenerative, and terminal disease was first described by the German psychiatrist and neuropathologist Alois Alzheimer in 1906. Several factors have been considered relevant for the AD pathogenesis and among these the most important is age. Construction of transgenic mice with tissue-specific acceleration of mitochondrial DNA mutagenesis.
During life small variations occurring in cellular metabolism and structure can modify the functional state of susceptible neurons, leading to dramatic or even lethal changes. Interestingly, late-onset AD is characterized not only by the neuropathological markers mentioned above, but also by vascular lesions, and hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance, adiposity, atherosclerosis and hypertension (Haan, 2006).Diabetes and AD are considered age-related diseases and are both increasing.
Phosphorylation is required for high-affinity binding of DBP, a yeast mitochondrial site-specific RNA binding protein. The Centers for Disease Control and Prevention predict that more than 29 million people in the US will be affected by diabetes by 2050, while the Alzheimer’s association forecasts that by this date, 11–16 million Americans will have AD (Han & Li, 2010). In fact, some studies revealed that 80% of patients with AD exhibited either impairments in glucose tolerance or frank diabetes (Schrijvers et al., 2010). Formation of the 3' end of yeast mitochondrial mRNAs occurs by site-specific cleavage two bases downstream of a conserved dodecamer sequence. The frequency of point mutations in mitochondrial DNA is elevated in the Alzheimer's brain. The inbalance between low and high glucose levels in T2D patients may be responsible for brain vascular damage and neurodegeneration thus facilitating the AD onset. A nucleoside triphosphate-regulated, 3' exonucleolytic mechanism is involved in turnover of yeast mitochondrial RNAs. The formation of amyloid aggregate occurs both in the intra- and extra-cellular environments; further the proteinaceous aggregates are strictly bound with membranes and calcified. X-ray fiber diffraction showed that amyloid fibrils contain beta-sheet structure lying orthogonally to the major fibril axis (Serpell, 2000).
They showed that the methyl carbons of Ala-21 and Ala-30 must be placed in groups of at least four with internuclear distances of less than 5.5 A. Although beta-sheets are the main constituent of the amyloid fibrils they are not the only structure present in the fibrils. Liquid state NMR, FTIR and CD measurements in Abeta40 have demonstrated the existence of a turn formed by the amino acids at position 26-29.
Little information is known about the Abeta42 fibril structure and many mutant peptides have been synthetized to obtain an explanation about its secondary structure.
Identification of a protein complex that binds to a dodecamer sequence found at the 3' ends of yeast mitochondrial mRNAs. The primary sequence of the peptide is well conserved in organisms and, in particular human and mouse IAPPs differ by only six amino acids but the latter does not form fibrils neither in vitro nor in vivo. As in Abeta, IAPP is non-toxic in its monomeric form but it exhibits high toxicity levels when it aggregates into beta-rich amyloid structures. Isolation and characterization of an NTP-dependent 3'-exoribonuclease from mitochondria of Saccharomyces cerevisiae. As in other amyloid peptides, the mechanism of fibrillation occurs through the formation of nuclei with a lag phase whose duration is concentration-dependent and proceeds by addition of monomers or oligomers to both fibril terminals.
The secondary structure of hIAPP mainly consists of unstructured regions, with small alpha-helical and beta-sheet components (Goldsbury et al., 2000).
In fact, recent studies have evidenced the importance of the residues in position 13-18 in the interaction leading to the formation of fibrils (Gilead & Gazit, 2008). Also the aromatic-aromatic interactions between residues 15, 23 and 37 seem to be important in amyloid formation althought not essential for fiber formation as evidenced using IAPP with a triple mutation (Marek et al., 2007).
The effect of oxidative stressThe brain has a high energy demand and, although it represents only 2% of body weight, it accounts for 20% of total body oxygen consumption. This energy requirement is largely driven by neuronal request of energy to maintain the ion gradients across the plasma membrane, which are critical for the generation of action potentials.
This intense energy requirement is continuous; even brief periods of oxygen or glucose deprivation result in neuronal death.
Diabetes mellitus leads to functional and structural changes in the brain, which appear to be most pronounced in the elderly. Increasing data support the idea that mitochondrial function declines with aging and in age-related diseases such as diabetes and AD.Normal glucose metabolism is required for the performance of cognitive functions, and impairments in glucose metabolism might contribute to cognitive dysfunction. Imaging studies have revealed that patients with AD and individuals at risk of developing this disease typically have reductions in glucose metabolism in temporal and parietal brain regions and hippocampus (Garrido et al., 2002).
These findings indicates that glucose metabolism and insulin signaling are important in normal brain function. The negative effect of impaired glucose metabolism on cognitive functioning can be caused by an increase in oxidative stress that is associated with mitochondrial dysfunction. Mitochondria are essential subcellular organelles for generating the energy that fuels normal cellular functioning.
At the same time, the mitochondria have a strategic task because, depending on environmental factors, they can decide whether to continue the healthy life of the cell or to terminate it by apoptosis activation. Mitochondria are essential for neuronal function because the limited glycolytic capacity of these cells makes them highly dependent on aerobic oxidative phosphorylation for their energetic needs. A variety of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced in vivo through both enzymatic and non-enzymatic routes. ROS include hydrogen peroxide, hydroxyl radical, superoxide ion and singlet oxygen, products of normal cellular respiration.
It is abundantly produced in the mitochondria during respiration cycles and reacts with the proteins, lipids, and nucleic acids during their production. Peroxynitrous acid is one of the major RNS found intracellularly and it is involved in the rapid nitration of aromatic residues of proteins, such as tyrosine, to give 3-nitrotyrosine, which may alter the protein structure.
In the absence of an appropriate compensatory response from the endogenous antioxidant network, the system becomes redox imbalanced, leading to the activation of a stress-sensitive intracellular signaling pathway and, in extreme conditions, to apoptosis.
Abnormal glucose metabolism can also increase the production of free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). Furthermore, levels of oxidized proteins are increased in the frontal and parietal lobes and in the hippocampus of patients with mild cognitive impairment compared with healthy controls, indicating that oxidative damage might occur early in the development of AD (Butterfield et al., 2007).
Minor modifications of the nucleic acid bases are repaired through base excision repair involving DNA glycosylase and AP endonuclease, which are located in nuclei and mitochondria. The progression of AD is associated with the diminished expression of these DNA repair enzymes (Nakabeppu et al., 2004). The accumulation of the oxidatively damaged nucleic acids and proteins likely exceeds the limit of cellular repair and detoxification mechanisms and leads to the onset or progression of diabetic and neurological pathologies.
Further evidence supporting this hypothesis has been obtained from studies of a mouse model of AD in which mutations in the genes encoding APP and presenilin 1 cause an increase in Abeta42 production. In these animals, lipid and protein peroxidation is evident at the disease onset (Matsuoka et al., 2001).
In a triple-transgenic animal model of AD, in which mice develop Abeta plaques, tangles and cognitive defects, a decrease in antioxidant capacity and an increase in lipid peroxidation were noted before the development of AD pathology (Resende et al., 2008).


Oxidative stress seems to affect APP either directly, by increasing APP levels, or indirectly, by modulating APP processing, and both mechanisms could increase levels of Abeta. Studies in transgenic mice and postmortem brain tissue from patients with AD suggest also that an increase in Abeta production leads to a rise in the production of ROS and that oxidative stress occurs early in the development of the disease. This suggests that diabetes and aging are risk factors for the neurodegeneration induced by this peptide. Mitochondrial dysfunction could be one of the common underlying mechanisms explaining the association between diabetes and AD.
Mitochondrial dysfunction and the resulting energy deficit trigger the onset of neuronal degeneration and death. Mitochondria serve also as high capacity Ca2+ sink, which allows them to follow the changes in cytosolic Ca2+ loads and helps in maintaining cellular Ca2+ homeostasis, required for normal neuronal function (Rizzuto et al., 2000).
Conversely, excessive Ca2+ uptake inside mitochondria has been shown to increase ROS production, inhibit ATP synthesis, release cytochrome C, and induce mitochondrial permeability transition (Brustovetsky et al., 2002).
The mitochondrial permeability transition (MPT) is defined as the sudden increase of inner mitochondrial membrane permeability to solutes of molecular mass lower than 1500 Da (Bernardi et al., 1994). Strong evidence now exists that the MPT is due to the opening of a nonselective megachannel (estimated to be 2–3 nm in diameter). Because the chemiosmotic theory is based on the impermeability of the inner mitocondrion membrane to solutes that are not specifically transported, MPT would collapse the mitochondrial membrane potential (??m) and uncouple the electron transport system from the production of ATP. Additionally, MPT results in mitochondrial swelling and can lead to the release of proapoptotic proteins. Some data show the existence of an age-related impairment of the respiratory chain and an uncoupling of oxidative phosphorylation in brain mitochondria isolated from Goto-Kakizaki (GK) rats, as model of T2D (Moreira et al., 2003). The maintenance of oxidative phosphorylation capacity is extremely important in the brain since a large amount of the energy required for the normal functioning of neurons is provided by mitochondria. Advanced glycation end products (AGE)Abnormal glucose metabolism and oxidative stress contribute to the formation of advanced glycation end products (AGE). This process occurs through the Maillard reaction or “non-enzymatic browning”, a complex series of reactions between reducing carbohydrates with lysine side chains and N-terminal amino groups of proteins.
This process initially leads to rather labile Schiff bases which as a rule rearrange to the more stable Amadori products.
Auto-oxidation of glucose leads to the formation of oxygen radicals, which are intermediates in the AGE pathway and the predominant source of endogenous AGEs. AGEs may exist as protein cross-links or as modification of the side chains of a single protein, and significantly alter protein conformations leading to protein inactivation. Numerous AGEs have been isolated and characterized by spectroscopic analysis after cleavage from the protein backbones. Examples of AGEs resulting from the single protein modification are pyrraline and N? -(carboxymethyl)lysine (CML), the lysine-residue modified products, and argpyrimidine, an arginine-residue modified protein. Furthermore, hippocampal neurons from patients with this neurodegenerative disease contain Abeta-positive, AGE-positive and RAGE positive granules.
Whether the modifications of Abeta and tau by AGEs are a primary or secondary event in AD is a controversial topic. Nevertheless, AGEs are widely accepted to be active participants in the progression of AD, since AGE-induced glycation of Abeta and tau protein has been shown to cause the Abeta aggregation and the formation of NFTs, respectively (Ledesma et al., 1994). Moreover, diabetic mice with cognitive impairments exhibit increased RAGE expression in neurons and glia compared with wild-type control mice (Toth et al. However, it should be pointed out that glycoxidation and oxidative stress are mutually dependent and reinforce each other. Thus, while the sources of oxidative stress may widely differ in diabetes and AD, and while a number of AGEs accumulate in both conditions, other AGEs found in diabetes have yet to be characterized in AD.6.
Antioxidant therapy in Alzheimer’s disease and diabetesGiven the importance of mitochondria as the primary source of oxidative stress in AD and diabetes, the use of antioxidants may also be useful. However, the broad occurrence of both diseases, the non-regenerative nature of the CNS and the fact that AD diagnosis often does not occur until late in the disease progression, suggest that the ideal antioxidant should be used as a prophylactic treatment for the aged population.
Oxidative stress is one of the earliest events in the neurological and pathological changes of AD, while the effects of oxidative stress are manifested in the slow accumulation of AGEs in diabetes. Thus, antioxidant therapy in combination with AGE inhibitor therapy may be effective approaches for AD and diabetes-related complications. Oxidative stress leads to irreversible protein aggregation and consequent neuronal degeneration in AD (Liu et al., 2007).
Advanced lipoxidation products, such as HNE, bind to phosphorylated tau protein to form paired helical filaments, accelerating the formation of neurofibrillary tangles. Oxidative stress also results in the covalent crosslinking of tau filaments to form large aggregates that are resistant to proteolytic cleavage. Larbig and coworkers reported a series of inhibitors for tau protein aggregation (Larbig et al., 2007).
Remarkably, thiazolium-based compounds, which are also AGE inhibitors and potentially useful for diabetic therapy, are effective inhibitors of tau aggregation. Common antioxidants include the vitamins A, C, and E, glutathione, and the enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Other antioxidants include lipoic acid, mixed carotenoids, coenzyme Q10, several bioflavonoids, antioxidant minerals (copper, zinc, manganese, and selenium), and the cofactors (folic acid; vitamins B1, B2, B6 and B12).
Vitamins A, C, and E are interesting antioxidant molecules because are diet-derived and directly detoxify free radicals.
Tocopherol is reconstituted when ascorbic acid recycles the tocopherol radical; dihydroascorbic acid, which is generated, is recycled by glutathione. Vitamin E, a component of the total peroxyl radical-trapping antioxidant system, reacts directly with peroxyl and superoxide radicals and singlet oxygen and protects membranes from lipid peroxidation (Weber et al., 1997).
A deficiency of vitamin E is concurrent with increased peroxides and aldehydes in many tissues.
There have been conflicting reports about vitamin E levels in diabetic animals and human subjects. Some attention to AGE inhibitors was focused on aminoguanidine, which blocks electrophilically activated 1,3-dicarbonyl compounds, the precursors of AGEs (Thomas et al. This compound was not approved by the US Food and Drug Administration due to adverse side effects in diabetic patients during Phase III clinical trials, and the search to find alternatives continues. Furthermore, these compounds are also good metal ion chelators and attenuate oxidative stress. N-acetylcysteine and lipoic acid act as inhibitors through attenuation of oxidative stress. While the AGE-inhibitory effect of these compounds is not clearly understood, a similar mechanism may operate in the case of AGEs. Carnosine, homocarnosine, and related compounds are potentially suitable as AGE inhibitors although further studies are needed to prove their efficacy in diabetes and AD (Reddy et al., 2005). Carnosine protects superoxide dismutase, catalase, and ?-crystallin from non-enzymatic glycation and protein crosslinking (Hipkiss, 2007). OPB-9195 inhibits AGE formation, especially pentosidine and N?-(carboxymethyl)lysine (CML), apparently through carbonyl trapping and metal ion chelation (Wada et al., 2001). Thiazolium-based compounds such as alagebrium chloride (ALT-711) and N-phenyacyl-1,3-thiazolium bromide (PTB) are effective AGE crosslink breakers, and are potentially useful drugs for diabetes and AD (Susic, 2007).
It should, however, be pointed out that the mechanisms of the action of the latter compounds are not clearly understood. In addition to their action as crosslink breakers of AGEs derived from 1,2-dicarbonyl compounds, they may also act as antioxidants through chelation of transition metal ions. The development of these drugs as therapeutics thus depends on the detailed understanding of their mechanisms of action. An alternative strategy involves removal of AGEs through the soluble receptors for AGEs (sRAGEs). Poor glycemic control in diabetes results in decreased concentrations of sRAGES, and upon insulin treatment, significant improvements in the levels of sRAGEs were observed, with concomitant decrease in AGEs (Devangelio et al., 2007).
Treatment of diabetic patients with rosiglitazone, a 2,4-thiazolidine dione derivative, results in increase of plasma sRAGEs, comparable to controls (Tan et al., 2007). However, the protective effect of sRAGEs has been questioned recently as their level are much higher in experimental animal models than those found in vivo, suggesting they may be only markers of inflammation (Humpert et al., 2007). Following the trend in using natural antioxidants, a recent paper has examined the effects of banana (Musa sp. The results indicate that fructosamine and AGEs formed during diabetes were inhibited in treated groups when compared with the diabetic group (Bhaskar et al., 2011). However, the results of clinical trials of antioxidant therapy are not clear because of duration of treatment as well as recruitment of patients at different stages of the diseases. In spite of inconsistency in the conclusions of clinical trials on the beneficial effects of antioxidants on these pathologies, epidemiological studies indicate that antioxidants may reduce the risk of their insurgence. It is suggested that a combination of antioxidants might be of greater potential benefit, especially if these agents work in different cellular compartments or have complementary activity (e.g.
If oxidative stress plays as important a role in AD and diabetes pathologies as the literature suggests, regular intake of antioxidants may be beneficial much before any sign or symptoms of the disease are visible. Insulin resistance, Tau hyperphosphorylation and the amyloid cascadeIn addition to being a modulator of food intake and energy homoeostasis, insulin is also an important neurothrophic factor.
It modulates brain activity, particularly for such high glucose demanding functions such as memory.
This form of diabetes is characterized by insulin resistance, hyperinsulinemia and impaired insulin signaling. Insulin resistance is the common link of the components of the much invoked metabolic syndrome (a cluster of high adiposity, abnormal glucose level, dyslipidemia, hypertension and high inflammation) and it is known to cause common diseases such as stroke, heart disease, and cancer.
Given the aging of the population and the epidemic of elevated insulin resistance, evidenced by the rise in elevated adiposity, prediabetes, and diabetes, it is alarming that insulin resistance could contribute to AD.
Many epidemiologic studies have found an association of elevated adiposity, insulin resistance, and T2D with cognitive impairment and dementia (Baker et al., 2011).
However, there are several important questions to be addressed for investigators studying the relation of insulin resistance and AD. Insulin receptors are expressed throughout the CNS, expecially in the hippocampus and cortex, even if their function in the brain is not fully understood.
Binding of insulin to its receptor activates the intrinsic tyrosine kinase activity of the cytoplasmic domain of the insulin receptor. This leads to autophosphorylation of tyrosine residues, which initiates several intracellular signaling cascades.
In the brain, insulin influences the release and reuptake of neurotransmitters, and also appears to improve learning and memory (Zhao et al., 2004).
The initial components of the insulin receptor signaling cascade in the brain are largely similar to those of the periphery. The downstream targets of the cascade are quite different, however, probably involving, among others, neuronal glutamate receptors (Zhao et al., 2004). Neurodegeneration and cognitive impairment in T2D and AD could be caused, in part, by damage to insulin receptor signaling (de la Monte & Wands, 2005). In fact, decreases in the sensitivity of such receptors are known to affect the expression and metabolism of Abeta and tau and impaired insulin receptor activity and hyperinsulinemia are observed in patients with AD and in animal models of this disease (Frolic et al., 1998). In addition, dysfunction of insulin receptor signaling is associated with impairments in Abeta oligomer clearance (Zhao, 2009) and increases the rate of NFT development (Lesort & Johnson, 2000). In fact, insulin transiently increases tau phosphorylation in primary cortical neurons, and hyperinsulinemia results in tau hyperphosphorylation in rat brains. Furthermore, insulin receptor substrate 2 knockout mice demonstrate typical pathological signs of T2D and have an increased number of NFTs in hippocampal neurons compared with control wild-type mice (Schubert, 2003). Insulin receptor signaling leads to the activation of two major signaling pathways, the mitogen-activated protein kinase (MAPK) pathway and the Akt signaling pathway. Thus, under normal conditions, insulin signaling via the insulin receptor leads to GSK-3? inactivation, whereas insulin resistance leads to GSK-3? dephosphorylation and activation (Balaraman et al., 2006). This enzyme is a metalloprotease responsible for insulin degradation and is also the main enzyme responsible for Abeta degradation (Farris et al., 2003). IDE is secreted to the extracellular space by microglial cells in the brain, where it degrades Abeta peptide, thus reducing the rate of aggregation and the plaque formation (Qiu et al., 1998).
IDE levels have been reported to be decreased in the brains of AD patients (Cook et al., 2003).
It has also been hypothesized that hyperinsulinemia in people with pre-diabetes and T2D effectively sequesters IDE, reducing Abeta peptide degradation.
This would increase levels of Abeta, and promote many of the pathological features associated with Alzheimer's disease. Supporting this model, the affinity for the binding of insulin to IDE is much greater than that for the Abeta (Qiuet al., 1997). In patients with Alzheimer's disease, IDE expression in the hippocampus is substantially reduced, with regards to controls, in particular among patients with the APOEvar epsilon4 genotype.
This latter observation could explain the potential interaction between diabetes and the APOEvar epsilon4 genotype in multiplying the risk of dementia (Cook et al., 2003).
Curiously, although the presence of the APOEvar epsilon4 is associated with an increased incidence of Alzheimer's disease, it seems that insulin resistance is only a significant risk factor for AD in those patients without APOEvar epsilon4 (Craft et al., 1998). This suggests that T2D could affect the pathogenesis of AD through mechanisms other than modulation of Abeta metabolism even if the underlying mechanisms for this association remain largely unknown (Takeda et al., 2011). FOXO: A common biomarker for AD and T2DThere is ongoing interest in defining mechanisms that govern insulin resistance and AD.
In particular, in presence of insulin, activated Akt translocates to the nucleus where directly phosphorylates FOXO at distinct sites stimulating interaction with 14-3-3 protein (Greer and Brunet, 2005).
This chaperone protein promotes the nuclear export and inhibits the nuclear import of FOXO proteins, driving the cells towards cell survival (van der Heide et al., 2004). In contrast, FOXO proteins, under conditions of oxidative stress, are phosphorylated by other protein kinases, including Mst1 and JNK, able to disrupt its interaction with 14-3-3, promoting FOXO nuclear translocation and thereby inducing cell death in neurons, thus opposing Akt’s action (Sunayama et al., 2005).
Thus, it is well established that Akt plays a key role in repressing FOXO transcriptional activity.
Immediately upstream from FOXO, the activity of Akt itself is governed by several protein kinases and phosphatases.
Akt regulates a variety of key physiological functions, and there is strong evidence suggesting that defective Akt signaling contributes to development of insulin resistance (Zdychova & Komers, 2005). However, although it is clear that FOXO governs multiple events in the insulin signaling cascade, mediating both positive and negative effects, the underlying molecular mechanisms are unknown. Some evidence has been reported that FOXO3 activation is also able to increase basal levels of Akt phosphorylation and kinase activity thus it is capable to activating its own inhibitor, providing a feedback regulation (Ni et al., 2007). Moreover, FOXO transcription factors are involved in both the insulin action and the cellular response to oxidative stress, thereby providing a potential integrative link between AD and insulin resistence (Manolopoulos et al., 2010).
Both insulin resistence and oxidative stress due to Abeta stimulus, may promote the transcriptional activity of FOXO proteins, resulting in hyperglycaemia and a further increased production of ROS. The consecutive activation of c-Jun N-terminal kinases and inhibition of Wingless (Wnt) signalling may result in the formation of Abeta plaques and tau protein phosphorylation. Wnt inhibition may also result in a sustained activation of FOXO proteins with induction of apoptosis and neuronal loss, thereby completing a vicious circle from oxidative stress, insulin resistence and hyperglycaemia back to the formation of ROS and consecutive neurodegeneration. Thus, it has been proposed that FOXO proteins may provide a potential molecular target for the treatment of both insulin resistence and AD (Manolopoulos et al., 2010).




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The definition of diabetes type 1




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