Elena L. Paley

Tryptamine induces axonopathy and mitochondriopathy mimicking neurodegenerative diseases via tryptophanyl-tRNA deficiency.

Neurodegeneration is induced by tryptamine, a human diet constituent, which easily crosses the blood/brain barrier. Tryptamine neurotoxicity, caused by tryptophanyl-tRNA synthetase (TrpRS) inhibition and downregulation leads to tryptophanyl-tRNA deficiency and synthesis of aberrant proteins. We identified axonal defects in hippocampus of tryptamine- treated mice similar to those observed in human brain of patients with Alzheimers disease, multiple sclerosis and epilepsy using anti-TrpRS site-directed antibodies. The axonal defects are characterized by swellings that accumulate abnormal amounts of helical filaments and amyloid. Tryptamine produced a decreased density of somatic mitochondria concomitant with neuronal loss in mouse hippocampus. In addition, tryptamine evoked accumulation and clustering of small mitochondria in mouse hippocampus causing axonal swellings. Similarly, mitochondrial fission, fusion and clustering were revealed in human neuronal cells after tryptamine administration. Moreover the tryptamine-induced mitochondrial neuropathology includes electron-dense deposits comprising helical fibrils, cristae disruption, cristolysis, mitochondrial swelling and mitochondria-derived vesicles. TrpRS+ helical filamentous tangles formed in both neuronal and kidney cells following tryptamine treatment suggest a tryptamine broad cytotoxic repertoire in damaging vital organs. Tryptamine elicited vesicularization of inner and outer mitochondrial membranes, axonal and cell membranes. Ultrastructurally, fragmentation of swollen degenerated mitochondria, small mitochondria clustering and neurofibrillary tangles are associated with axonal membrane protrusions attributed as neuritic swellings at a lower magnification. TrpRS+ axonal swellings associated with neuropathology of patients and tryptamine-treated human cells suggest that under toxic concentrations, tryptamine is implicated as a causative agent in neurodegeneration resembling that defining a number of human diseases.

Tryptamine induces tryptophanyl-tRNA synthetase-mediated neurodegeneration with neurofibrillary tangles in human cell and mouse models

The neuropathological hallmarks of Alzheimer’s disease (AD) and other taupathies include neurofibrillary tangles and plaques. Despite the fact that only 2–10% of AD cases are associated with genetic mutations, no nontrasgenic or metabolic models have been generated to date. The findings of tryptophanyl-tRNA synthetase (TrpRS) in plaques of the AD brain were reported recently by the authors. Here it is shown that expression of cytoplasmic-TrpRS is inversely correlated with neurofibrillary degeneration, whereas a nonionic detergent-insoluble presumably aggregated TrpRS is simultaneously accumulated in human cells treated by tryptamine, a metabolic tryptophan analog that acts as a competitive inhibitor of TrpRS. TrpRS-N-terminal peptide self-assembles in double-helical fibrils in vitro. Herein, tryptamine causes neuropathy characterized by motor and behavioral deficits, hippocampal neuronal loss, neurofibrillary tangles, amyloidosis, and glucose decrease in mice. Tryptamine induced the formation of helical fibrillary tangles in both hippocampal neurons and glia. Taken together with the authors’ previous findings of tryptamine-induced nephrotoxicity and filamentous tangle formation in kidney cells, the author’s data indicates a general role of tryptamine in cell degeneration and loss. It is concluded that tryptamine as a component of a normal diet can induce neurodegeneration at the concentrations, which might be consumed along with food. Tryptophan-dependent tRNAtrp aminoacylation catalyzed by TrpRS can be inhibited by its substrate tryptophan at physiological concentrations was demonstrated. These findings indicate that the dietary supplementation with tryptophan as a tryptamine competitor may not counteract the deleterious influence of tryptamine. The pivotal role of TrpRS in protecting against neurodegeneration is suggested, providing an insight into the pathogenesis and a possible treatment of neurodegenerative diseases.

Hypoxia signature of splice forms of tryptophanyl-tRNA synthetase marks pancreatic cancer cells with distinct metastatic abilities.

Objectives: Pancreatic cancer is one of most deadly because of its aggressive growth and high metastatic ability that correlates with intratumoral hypoxia. Earlier diagnosis and prognosis marker of pancreatic cancer is not yet available. In colorectal cancer, protein biosynthesis enzyme, tryptophanyl-tRNA synthetase (TrpRS), is up-regulated in good-prognosis tumors and down-regulated in metastatic poor-prognosis tumors. Tryptophanyl-tRNA synthetase status in pancreatic cancer is unknown. To correlate metastatic ability with hypoxia and TrpRS as a possible prognostic marker, we examined mRNA and protein expression in 2 human pancreatic cancer cell lines with different metastatic abilities and TrpRS levels using our site-specific monoclonal antibodies directed to conformation-dependent epitopes on pancreatic TrpRS. Methods: Pancreatic MIAPaCa-2, Panc-1, cervical HeLa, and prostate cancer PC-3 cells were cultivated under normoxia or in hypoxic chamber. Expression of full-length TrpRS, antiangiogenic TrpRS, cyclin B1, hypoxia-inducible factor 1&agr;, and Glut-1 was determined with reverse transcriptase-polymerase chain reaction, immunoblotting, and immunocytochemistry. Results: We demonstrate that hypoxia regulates differentially TrpRS splice forms. Pronounced down-regulation of full-length TrpRS by hypoxia is concomitant with higher metastatic ability. Conclusions: Tryptophanyl-tRNA synthetase down-regulation by hypoxia may be a factor responsible for low TrpRS in tumors with high metastatic ability. Tryptophanyl-tRNA synthetase recognizability is important for pancreatic cancer prognosis and as a new target for metastasis treatment.

Tryptamine-Induced Tryptophanyl-tRNAtrp Deficiency in Neurodifferentiation and Neurodegeneration Interplay: Progenitor Activation with Neurite Growth Terminated in Alzheimer's Disease Neuronal Vesicularization and Fragmentation

Tryptophanyl-tRNA synthetase (TrpRS) catalyzes tryptophanyl-tRNAtrp formation. At concentrations exceeding tryptophan, tryptamine inhibits TrpRS. This leads in tryptophanyl-tRNA deficiency and synthesis of aberrant proteins. Tryptamine presents in food and crosses blood-brain barrier. The purpose of this study is to test the hypothesis that tryptamine-induced changes in cell and animal models correlate with Alzheimers disease (AD) manifestations. Tryptamine prevented growth of human neuroblastoma. Epithelioids recovered growth in tryptamine-free medium, while neuroblasts died. Tryptamine induced epithelioid differentiation forming synaptic vesicles, neuritic contacts, and TrpRS+ axons in stable sublines. A fraction of epithelioids was adhered to satellite cells via trypsin-resistant interdigitating junctions. Tryptamine stimulated satellite division and differentiation into neurons, transitional cell variants and neuroblasts able to repopulate. Both tryptamine-inhibited and hypoxia-downregulated TrpRS translocates into cytoplasmic extensions. TrpRS is secreted into extracellular space as a free protein or within vesicles extended from cytoplasm and then pinched-off from plasma membrane of tryptamine-treated cells. Extracellular vesicles fuse in congophilic TrpRS+ plaques in tryptamine-treated culture and AD brain. TrpRS prominent immunoreactivity is associated with plasma and vesicle membranes of satellites and AD brain degenerated neurons. Tryptamine-modified mouse brain expresses amyloid and abnormal filaments in extracellular and neuronal plasma membrane vesicles. Radiolabeled tryptamine, tryptophan and serotonin uptake was 10-fold lower in tryptamine-resistant compared to tryptamine-sensitive cells. In both variants, tryptamine uptake exceeded tryptophan uptake within 2-h assuring TrpRS inhibition. Here, tryptophanyl-tRNAtrp deficiency implicates in both neurite growth and termination/collapse. Neurite growth termination prompts TrpRS+ vesicularization. TrpRS+ vesicles contribute in neuronal fragmentation and fibrillar-vesicular congophilic plaques in AD brain.

Geographical Distribution and Diversity of Gut Microbial NADH:Ubiquinone Oxidoreductase Sequence Associated with Alzheimer’s Disease

Earlier we reported induction of neurotoxicity and neurodegeneration by tryptophan metabolites that link the metabolic alterations to Alzheimers disease (AD). Tryptophan is a product of Shikimate pathway (SP). Human cells lack SP, which is found in human gut bacteria exclusively using SP to produce aromatic amino acids (AAA). This study is a first attempt toward gene-targeted analysis of human gut microbiota in AD fecal samples. The oligonucleotide primers newly-designed for this work target SP-AAA in environmental bacteria associated with human activity. Using polymerase chain reaction (PCR), we found unique gut bacterial sequence in most AD patients (18 of 20), albeit rarely in controls (1 of 13). Cloning and sequencing AD-associated PCR products (ADPP) enables identification of Na(+)-transporting NADH: Ubiquinone reductase (NQR) in Clostridium sp. The ADPP of unrelated AD patients possess near identical sequences. NQR substrate, ubiquinone is a SP product and human neuroprotectant. A deficit in ubiquinone has been determined in a number of neuromuscular and neurodegenerative disorders. Antibacterial therapy prompted an ADPP reduction in an ADPP-positive control person who was later diagnosed with AD-dementia. We explored the gut microbiome databases and uncovered a sequence similarity (up to 97%) between ADPP and some healthy individuals from different geographical locations. Importantly, our main finding of the significant difference in the gut microbial genotypes between the AD and control human populations is a breakthrough.

Towards an Integrative Understanding of tRNA Aminoacylation–Diet–Host–Gut Microbiome Interactions in Neurodegeneration

Transgenic mice used for Alzheimer’s disease (AD) preclinical experiments do not recapitulate the human disease. In our models, the dietary tryptophan metabolite tryptamine produced by human gut microbiome induces tryptophanyl-tRNA synthetase (TrpRS) deficiency with consequent neurodegeneration in cells and mice. Dietary supplements, antibiotics and certain drugs increase tryptamine content in vivo. TrpRS catalyzes tryptophan attachment to tRNAtrp at initial step of protein biosynthesis. Tryptamine that easily crosses the blood–brain barrier induces vasculopathies, neurodegeneration and cell death via TrpRS competitive inhibition. TrpRS inhibitor tryptophanol produced by gut microbiome also induces neurodegeneration. TrpRS inhibition by tryptamine and its metabolites preventing tryptophan incorporation into proteins lead to protein biosynthesis impairment. Tryptophan, a least amino acid in food and proteins that cannot be synthesized by humans competes with frequent amino acids for the transport from blood to brain. Tryptophan is a vulnerable amino acid, which can be easily lost to protein biosynthesis. Some proteins marking neurodegenerative pathology, such as tau lack tryptophan. TrpRS exists in cytoplasmic (WARS) and mitochondrial (WARS2) forms. Pathogenic gene variants of both forms cause TrpRS deficiency with consequent intellectual and motor disabilities in humans. The diminished tryptophan-dependent protein biosynthesis in AD patients is a proof of our model-based disease concept.

Neuro-degeneration: Inhibition of protein biosynthesis, food and infections

A spectrum disorders (ASD) represent a heterogeneous cluster of clinical phenotypes that may vary in age of onset, but are classically diagnosed by adolescence or early adulthood at latest. The possibility that development of late life ASD may occur after this age has been poorly explored. Several recent studies have suggested that late life onset of ASD symptoms can develop in frontotemporal dementia, but otherwise have not been linked to the development of neurodegenerative disorders such as Alzheimer’s disease (AD) or mild cognitive impairment (MCI). In order to more fully characterize the possibility of late life emergence of ASD symptoms in MCI and AD, we surveyed the caregivers of 140 subjects with late-life cognitive impairment from the University of Kentucky Alzheimer’s Disease Center Longitudinal Cohort using the GARS-II. Eighty-one caregivers returned the survey for a response rate of 58%. For subjects whose age of onset of cognitive decline was known, autism index ratings based on the sum of the three GARS-II subscale standard scores were associated with age at onset. Subjects with the highest index ratings (Possible/Very likely, n=14) reported significantly (statistically and clinically) younger age at onset than those who scored in the ‘Unlikely’ range (n=49): 68.2±9.3 vs. 74.9±7.9 (p=0.0088). This remains true when only the dementia cases are considered: 67.7±9.4 (Possible/Very likely, n=13) vs. 74.0±8.8 (Unlikely, n=33): (p=0.038). These data demonstrate that ASD symptoms are seen in conjunction with late-life degenerative dementia of all types and are more prevalent in those with early vs. late onset dementia. It is possible that lifelong subclinical ASD tendencies, might manifest only when neurological function is compromised by the development of even the mildest of pathologic insults in geriatric years. Further work elucidating a potentially complex interplay between ASD and late life dementia could shed much light on our appreciation of preclinical forms of ASD, identify key areas of shared neuroanatomic involvement between ASD and late life dementias, and further provide valuable insights that might hasten the development of therapeutic strategies for both ASD and late life neurodegenerative disorders. Gregory A. Jicha, J Alzheimers Dis Parkinsonism 2013, 3:4 http://dx.doi.org/10.4172/2161-0460.S1.004A to the clinical literature many of children with Autism Spectrum Disorders (ASD) seem to be obsessed with mechanical tools, machines, and physical systems and experimental studies imply that they have accelerated or superior development in this domain. The purpose of this study is to observe and analyze the contents of drawings of high-functioning children with ASD who are obsessed with technology/physics-related tools and objects to see the effects of this physics fascination on the contents and patterns of their drawings. In this multiple case report children with ASD who were referred to occupational therapy clinics by child psychiatrists are studied. The drawings used were obtained during occupational therapy sessions. We discuss each patient’s particular case and the content of his drawings. Each child has at least one particular technology/physicsrelated feature as the dominant subject of his drawings. The feature is also the object of the child’s daily obsessive preoccupation. While most of these children have lower than normal drawing skills, they usually are well capable of drawing the object of obsession skillfully and with details. It seems that this physics-related fascination not only conveys these children’s higher levels of understanding of physical representations as already shown in the literature, but they also enhance the child’s drawing skills in that particular area. Sara Nakhai, J Alzheimers Dis Parkinsonism 2013, 3:4 http://dx.doi.org/10.4172/2161-0460.S1.004B amines, decarboxylated analogs of amino acids act as competitive inhibitors of aminoacyl-tRNA synthetases, enzymes of protein biosynthesis. At high concentration, biogenic amines can induce cell death via arrest of protein biosynthesis. Human cells and also microorganisms associated with food products and environment produce biogenic amines. The content of biogenic amines such as tyramine, histamine and tryptamine is high in common food products. Tryptamine appears as a suitable etiological factor killing neurons in human brain because in contrast to tyramine and histamine, tryptamine easily crosses blood-brain barrier (i) and tryptophan is not synthesized in human body and is a least available amino acid in food (ii). Thus the tryptamine inhibitory effect cannot be easily compensated by tryptophan. By other words, increased tryptamine prevents incorporation of tryptophan in proteins. The blockage of protein biosynthesis leads in cell death. The neuronal death is a major feature of all neurodegenerative diseases. Our experiments on human neuronal cells and mice demonstrate a massive neuronal loss induced by tryptamine at the concentrations inhibiting tryptophanyl-tRNA synthetase. Moreover amyloidosis and formation of neurofibrillary tangles, the manifestations of neurodegeneration were also induced by tryptamine in human neuronal cultured cells and mouse brain. Histologically manifestations induced by tryptamine are similar to those we found in autopsy brain of patients with Alzheimer’s disease. For further analysis of samples of Alzheimer’s disease patients and healthy controls we developed specific test, which reveals a link between microorganisms and disease. Elena Paley, J Alzheimers Dis Parkinsonism 2013, 3:4 http://dx.doi.org/10.4172/2161-0460.S1.004M oxidases (MAOs) are flavoenzymes bound to the outer mitochondrial membrane and are responsible for the oxidative deamination of neurotransmitters and dietary amines and trace of amines. Two isoforms, namely MAO-A and MAO-B, have been identified on the basis of their amino acid sequences, three dimensional structure, substrate preference, and inhibitor selectivity. MAO-A has a higher affinity for serotonin and noradrenaline, whereas MAO-B preferentially deaminates phenylethylamine and benzylamine, this leads to the rapid degradation of these molecules and ensure that the proper functioning of synaptic neurotransmission, regulation of emotional behaviors and other brain functions. The byproduct of MAO-mediated reactions includes several chemical species with neurotoxic potential, such as hydrogen peroxide, ammonia and aldehydes. As a consequence of prolonged excessive activity of these enzymes may lead to mitochondrial damages and neurodegenerative disturbances/disorder MAOIs introduced into clinical practice during 1960’s were abandoned due to adverse effects, Such as hepatotoxicity, orthostatic hypotension, and the so-called “cheese effect”, which was characterized by hypertensive crisis. Then it was understood that most of the adverse effects are due to non-selective inhibition of MAO-isoforms. This has led to an intensive search for novel MAO inhibitors (MAOIs), selective towards isoforms, and this effort has increased considerably in recent years. Selective MAO-A inhibitors such as clorgyline (irreversible) and moclobemide (reversible) are used in the treatment of neurological disorders such as depression, whereas the selective and irreversible MAO-B inhibitors such as selegiline and rasagiline are useful in the treatment of Parkinson’s and Alzheimer’s diseases. Most of the inhibitors in the clinical practice are either selective & irreversible or non-selective reversible with few exceptions. According to WHO, depression is a common phenomenon affecting about 350 million people worldwide and can lead to suicide. Suicide in an estimated 1 million deaths every year depression related suicides (on WHO site). On the other side it is estimated that Neurodegenerative diseases will become the world’s second leading cause of death by the middle of this century. The cost of illness and economic burden due to depression and neurodegenerative disorders were estimated to be

SYNTHETIC PEPTIDE CORRESPONDING TO THE AMINO-TERMINAL REGION OF THE HUMAN TRYPTOPHANYL-tRNA SYNTHETASE, A COMPONENT OF ALZHEIMER'S DISEASE SPECIAL CONGOPHLIC PLAQUES AGGREGATES IN VITRO TO FORM AMYLOID-LIKE FIBRILS

91000 and

Mapping and molecular characterization of novel monoclonal antibodies to conformational epitopes on NH2 and COOH termini of mammalian tryptophanyl-tRNA synthetase reveal link of the epitopes to aggregation and Alzheimer's disease

100 billion/annum respectively for a US and will be many-fold higher for our nation (on WHO site). India with total population of more than 120 million has a greater concern due to increasing number of cases of depression and neurodegenerative disorders (on WHO site). More than 60% of the population in India are in rural settings and are having restricted accesses to their medication needs. Moreover poor socio-economic condition, increase in life expectancy (63/66) etc compounding the situation. We are in greater need of cheaper drugs for the treatment of depression and neurodegenerative disorders and means to make it available for the people in remote rural settings. , J Alzheimers Dis Parkinsonism 2013, 3:4 http://dx.doi.org/10.4172/2161-0460.S1.004I recent years a large number of experimental observations have suggested a relationship between cholesterol homeostasis and Alzheimer’s disease (AD). Consequently, statins have been evaluated as neuroprotective drugs for the prevention and treatment of AD, showing benefit in several experimental and epidemiological studies. However, these positive effects are generally not in accordance with placebo-controlled randomized clinical trials (CT). One of the reasons for the failure is the selection of the statin for the CT, especially because the commercially available statins were developed for their plasma-cholesterol lowering effects. Neuron BioPharma is developing a discovery program for the identification of statins especially designed for neuroprotection. To this end, the molecules have been rationally designed, studied by in silico methods, synthesized in small quantities and evaluated for neuroprotective activity by using the exclusive Neuron BioPharma experimental platform that integrates in vitro, cellular and animal models for the study of AD. In this regard, a group of novel neuroprotective statins have been identified and developed, wherein the most advanced derivative (NST0037) will start the First-in-Human phase during this year. The identification and evaluation of a novel statin with a higher neuroprotective profile than the commercial available statins could open a new insight in the AD treatment field, and the use of neuroprotective statins could be considered as a new strategy to modify the disease progression. Moreover, the identification of neuroprotective statins could increase the possibility of success in CT for AD and, consequently, to define a new biomarker scenario to study the AD progression. Javier S. Burgos, J Alzheimers Dis Parkinsonism 2013, 3:4 http://dx.doi.org/10.4172/2161-0460.S1.004I impairments are a primary symptom of many neurodevelopmental disorders, and an associated symptom of autism. Analogous cross-species tasks of cognition that use similar equipment and methods could advance the search for cognitive enhancers. We employed an innovative touch screen technology for mice to design a complex cortically dependent task that requires inhibitory control, cognitive flexibility and relational learning. We assessed the inbred strain, BTBR T+tf/J (BTBR), a mouse model of autism with social and cognitive deficits, as compared to a control strain, C57BL/6J (B6), on a simple visual discrimination task and on transitive inference (TI). BTBR performed normally on pairwise discrimination and reversal. BTBR displayed deficits on components of TI, specifically when four premise pairings were interspersed during inference training reviews, which require more complex, flexible integrations of knowledge. Performance by BTBR was worse than B6 on the end paired A > E, similar to adults affected by an autism spectrum disorder. Our data demonstrate that mice are capable of complex visual discriminations and higher order TI tasks using methods and equipment similar to those used in humans and non-human primates, and that deficits may be detected in mouse models of autism using the touch screen technology. Jill L. Silverman, J Alzheimers Dis Parkinsonism 2013, 3:4 http://dx.doi.org/10.4172/2161-0460.S1.004T can cause a variety of social problems. Those who have been traumatized may feel like no one understands them, be anxious and distrustful of others, feel awkward socially, and turn to isolating themselves. These problems make it challenging for clinicians to connect with and to treat these types of patients. However, the psychotherapy literature clearly shows that the therapeutic relationship is the foundation of treatment, and without it, it becomes much more difficult to help patients. The purpose of this presentation is to address this problem and to offer a model to aid in the development and maintenance of the therapeutic relationship with those who have been traumatized. We will review the social challenges faced by traumatized individuals, explore the topic of evidence-based relationships, and then discuss the model itself. The model emphasizes the core skills of empathy (as described by Carl Rogers), meta communication (i.e. discussing the communication and the relationship itself), and collaboration. The approach is designed to be broadly applicable for anyone in the health related professions who work with those who have been traumatized. Future directions for the model will also be discussed. Edward MacPhee, J Alzheimers Dis Parkinsonism 2013, 3:4 http://dx.doi.org/10.4172/2161-0460.S1.004T brain consists of different structures that are continuously interacting to regulate and control bodily activities, interpret sensory impulses and help organs and muscles function. It is also known to control consciousness, thought, memory and emotion. During acute and chronic clinical depression specific brain structures are altered both in function and size. For further research on this matter a metaanalysis was conducted by reviewing 25 medical studies of the adult population, the focus was specifically in the changes involving the Amygdala, Hippocampus, Prefrontal Cortex and Anterior Cingulate Cortex. Out of the 25 articles, 8 found major changes in the hippocampus, 10 in areas of the prefrontal cortex, 7 in the amygdala and 4 in the anterior cingulate cortex. In general the major overlap involved changes in the amygdala and hippocampus. The importance of focusing on structural changes involved in clinical depression is not only to help in creating major awareness of this pathology but more specifically to help in the future aim of its treatment. We recognize that the prevalence of clinical depressions diagnosis has grown from 3.33% in 1991-1992 to 10% in 2012 in the United States of America. Thus, the importance of recognizing and treating depression can improve the quality of life in 1/10 patients in the United States of America today. Adriana Garza Lopez, J Alzheimers Dis Parkinsonism 2013, 3:4 http://dx.doi.org/10.4172/2161-0460.S1.004C with neurological and behavioral problems are commonly given the diagnosis of Autistic Spectrum Disorders (ASD), which is a highly heterogeneous group of patients manifesting autistic-like behaviors. A vast majority but not all ASD children have classic or typical autism. In that regard, we recently identified an autoimmune subset of autism and referred to it as “Autoimmune Autistic Disorder (AAD).” In this report, we describe laboratory studies for the identification and characterization of AAD. Subjects in the study were autistic children and normal healthy children. Blood samples of these children and cerebrospinal fluid (CSF) sample of some children were analyzed. These specimens were analyzed autoimmune markers that included brain autoantibodies, pro-inflammatory cytokines and virus/vaccine serology. Laboratory methods included enzyme-linked immunosobent assay (ELISA) and protein immunoblotting assay. We found experimental evidence for the presence of autoimmune markers in children with autism but not in healthy children. First, autistic children harbored brain-specific autoantibodies [e.g. antibodies to myelin basic protein (anti-MBP) and antibodies to caudate nucleus (anti-CN)]. Secondly, autistic children had elevated levels of pro-inflammatory cytokines (e.g. interferongamma and interleukin-12), acute-phase protein (e.g. C-reactive protein) and S-100 protein. Thirdly, autistic children harbored elevated levels of antibodies to measles virus (but not CMV, EBV, HHV-6, mumps or rubella virus) and measles/mumps/rubella (MMR) vaccine (but not Hepatitis B, DT or DPT). CSF samples of some autistic children were also positive for antibodies to brain antigens and measles virus. Of clinical importance to autoimmune pathogenesis, we found a positive correlation between brain autoantibodies (anti-MBP) and virus serology (anti-measles virus). Collectively, these laboratory findings provide scientific evidence in support of an autoimmune mechanism of pathogenesis of autism. This mechanism was found in a vast majority of children with autism an autoimmune subset henceforth referred to as “Autoimmune Autistic Disorder (AAD)”. Since health conditions involving autoimmunity are commonly regarded as autoimmune diseases and treated medically, we suggest that autism or AAD be considered as a medical condition and be treated with immune modulation therapy. Vijendra K. Singh, J Alzheimers Dis Parkinsonism 2013, 3:4 http://dx.doi.org/10.4172/2161-0460.S1.004A disease is accompanied by memory deficits. These deficits could be the consequence of changes in adult dentate gyrus neurogenesis. As a first step to analyze those changes we have used a transgenic mouse model that shows an impaired neurogenesis upon over expression of GSK3, a protein kinase that could be activated in Alzheimer disease (AD). Our results have indicated a deficient morphology in adult newborn neurons that are unable to connect properly with the preexisting neurons. These observations found in the mouse model were compared to the features found in the brain of Alzheimer disease patients and some similarities were found. Our results suggest that an impaired neurogenesis may be responsible of the memory deficits found in AD patients. Jesus Avila, J Alzheimers Dis Parkinsonism 2013, 3:4 http://dx.doi.org/10.4172/2161-0460.S1.004

Chaperon-like Activation of Serum-Inducible Tryptophanyl-tRNA Synthetase Phosphorylation through Refolding as a Tool for Analysis of Clinical Samples

INTRODUCTION. Tryptophanyl-tRNA synthetase (TrpRS, EC 6.1.1.2), a phosphoprotein[1] is a member of a family of aminoacyl-tRNA synthetases catalyzing the esterification of an amino acid to its cognate tRNA. TrpRS belongs to the class I synthetases sharing two amino acid consensus motifs HIGH and KMSKS. In addition, a conserved consensus domain of 46 amino acids called WHEP-TRS is present at the N-terminal extremity of TrpRS (amino acids 19 to 64 of the human TrpRS) in a number of higher eukaryotic aminoacyl-tRNA synthetases. This domain contains a central alpha-helical region (helix-turn-helix) and its role remains unclear. We have characterized TrpRS in human brain and revealed new type plaque-associated TrpRS in Alzheimer’s disease brain sections. The peptides corresponding to TrpRS were synthesized and their aggregation behavior was analyzed. METHODS. Monoclonal and polyclonal antibodies to human recombinant and bovine purified TrpRS were used for immunohistochemical analysis of brain sections of Alzheimer’s diseases patients and controls. Two polypeptides corresponding to regions of N-terminal (19 amino acids) and C-terminal (24 amino acids) sequence of human TrpRS were synthesized. Congo Red staining and birefringence were examined for anti-TrpRS immunostained brain sections and synthetic peptides.