Altered Serum IgG Levels to a-Synuclein in Dementia with Lewy Bodies and Alzheimer’s Disease.

Natural self-reactive antibodies in the peripheral blood may play a considerable role in the control of potentially toxic proteins that may otherwise accumulate in the aging brain. The significance of serum antibodies reactive against asynuclein is not well known. We explored serum IgG levels to monomeric a-synuclein in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) with a novel and validated highly sensitive ELISA assay. Antibody levels revealed stark differences in patients compared to healthy subjects and were dependent on diagnosis, disease duration and age. Anti-asynuclein IgG levels were increased in both patient groups, but in early DLB to a much greater extent than in AD. Increased antibody levels were most evident in younger patients, while with advanced age relatively low levels were observed, similar to healthy individuals, exhibiting stable antibody levels independent of age. Our data show the presence of differentially altered IgG levels against a-synuclein in DLB and AD, which may relate to a disturbed a-synuclein homeostasis triggered by the disease process. These observations may foster the development of novel, possibly preclinical biomarkers and immunotherapeutic strategies that target a-synuclein in neurodegenerative disease.Fil: Koehler, Niklas. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Stransky, Elke. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Shing, Mona. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Gaertner, Susanne. Department of Psychiatry and Psychotherapy, EBERHARD-KARLS-UNIVERSITY;Fil: Meyer, Mirjam. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Schreitmueller, Brigitte. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Leyhe, Thomas. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Laske, Cristoph. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Maetzler, Walter. Department of Neurodegeneration. HERTIE INSTITUTE FOR CLINICAL BRAIN RESEARCH;Fil: Kahle, Philipp. FUNCTIONAL NEUROGENETICS. HERTIE INSTITUTE FOR CLINICAL;Fil: Celej, Maria Soleda. MAX-PLANCK-INSTITUTE FOR BIOPHYSICAL CHEMISTRY; Consejo Nacional de Invest.cientif.y Tecnicas. Centro Cientifico Tecnol.conicet - Cordoba. Centro de Invest.en Qca.biol.de Cordoba (p);Fil: Jovin, Thomas M.. MAX-PLANCK-INSTITUTE FOR BIOPHYSICAL CHEMISTRY;Fil: Fallgatter, Andreas. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Batra, Anil. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Buchkremer, Gherard. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Schott, Klauss. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY;Fil: Richartz-Salzburger, Elke. Department of Psychiatry and Psychotherapy. EBERHARD-KARLS-UNIVERSITY

Differential blood DNA methylation across Lewy body dementias

IntroductionDementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by cognitive alterations, visual hallucinations, and motor impairment. Diagnosis is based on type and timing of clinical manifestations; however, determination of clinical subtypes is challenging. The utility of blood DNA methylation as a biomarker for Lewy body disorders (LBD) is mostly unexplored.MethodsWe performed a cross-sectional analysis of blood methylation in 42 DLB and 50 PDD cases applying linear models to compare groups and logistic least absolute shrinkage and selection operator regression to explore the discriminant power of methylation signals.ResultsDLB blood shows differential methylation compared to PDD. Some methylation changes associate with core features of LBD. Sets of probes show high predictive value to discriminate between variants.DiscussionOur study is the first to explore LBD blood methylation. Despite overlapping clinical presentation, we detected differential epigenetic signatures that, if confirmed in independent cohorts, could be developed into useful biomarkers

Alpha-Synuclein Levels in Blood Plasma Decline with Healthy Aging

There is unequivocal evidence that alpha-synuclein plays a pivotal pathophysiological role in neurodegenerative diseases, and in particular in synucleinopathies. These disorders present with a variable extent of cognitive impairment and alpha-synuclein is being explored as a biomarker in CSF, blood serum and plasma. Considering key events of aging that include proteostasis, alpha-synuclein may not only be useful as a marker for differential diagnosis but also for aging per se. To explore this hypothesis, we developed a highly specific ELISA to measure alpha-synuclein. In healthy males plasma alpha-synuclein levels correlated strongly with age, revealing much lower concentrations in older (avg. 58.1 years) compared to younger (avg. 27.6 years) individuals. This difference between the age groups was enhanced after acidification of the plasmas (p<0.0001), possibly reflecting a decrease of alpha-synuclein-antibody complexes or chaperone activity in older individuals. Our results support the concept that alpha-synuclein homeostasis may be impaired early on, possibly due to disturbance of the proteostasis network, a key component of healthy aging. Thus, alpha-synuclein may be a novel biomarker of aging, a factor that should be considered when analyzing its presence in biological specimens.Fil: Koehler, Niklas K. U.. Eberhard-Karls-University Tübingen. Department of Psychiatry and Psychotherapy; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Stransky, Elle. Eberhard-Karls-University Tübingen. Department of Psychiatry and Psychotherapy; AlemaniaFil: Meyer, Mirjam. Eberhard-Karls-University Tübingen. Department of Psychiatry and Psychotherapy; AlemaniaFil: Gaertner, Susanne. Eberhard-Karls-University Tübingen. Department of Psychiatry and Psychotherapy; AlemaniaFil: Shing, Mona. Eberhard-Karls-University Tübingen. Department of Psychiatry and Psychotherapy; AlemaniaFil: Schnaidt, Martina. Zentrum für Klinische Transfusionsmedizin; AlemaniaFil: Celej, Maria Soledad. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Quimica Biológica; Argentina. Institute for Biophysical Chemistry. Laboratory for Cellular Dynamics, Max-Planck; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (p); ArgentinaFil: Jovin, Thomas M.. Institute for Biophysical Chemistry. Laboratory for Cellular Dynamics, Max-Planck; AlemaniaFil: Leyhe, Thomas. Eberhard-Karls-University Tübingen. Department of Psychiatry and Psychotherapy; Alemania. Psychiatric University Hospital. Center of Old Age Psychiatry; AlemaniaFil: Laske, Christoph . Eberhard-Karls-University Tübingen. Department of Psychiatry and Psychotherapy; Alemania. German Center for Neurodegenerative Diseases; AlemaniaFil: Batra, Anil. Eberhard-Karls-University Tübingen. Department of Psychiatry and Psychotherapy; AlemaniaFil: Buchkremer, Gerhard. Eberhard-Karls-University Tübingen. Department of Psychiatry and Psychotherapy; AlemaniaFil: Fallgatter, Andreas J.. Eberhard-Karls-University Tübingen. Department of Psychiatry and Psychotherapy; AlemaniaFil: Wernet, Dorothee. Zentrum für Klinische Transfusionsmedizin; AlemaniaFil: Richartz Salzburger, Elke. Eberhard-Karls-University Tübingen. Department of Psychiatry and Psychotherapy; Alemani

Altered serum IgG levels to α-synuclein in dementia with Lewy bodies and Alzheimer's disease.

Natural self-reactive antibodies in the peripheral blood may play a considerable role in the control of potentially toxic proteins that may otherwise accumulate in the aging brain. The significance of serum antibodies reactive against α-synuclein is not well known. We explored serum IgG levels to monomeric α-synuclein in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) with a novel and validated highly sensitive ELISA assay. Antibody levels revealed stark differences in patients compared to healthy subjects and were dependent on diagnosis, disease duration and age. Anti-α-synuclein IgG levels were increased in both patient groups, but in early DLB to a much greater extent than in AD. Increased antibody levels were most evident in younger patients, while with advanced age relatively low levels were observed, similar to healthy individuals, exhibiting stable antibody levels independent of age. Our data show the presence of differentially altered IgG levels against α-synuclein in DLB and AD, which may relate to a disturbed α-synuclein homeostasis triggered by the disease process. These observations may foster the development of novel, possibly preclinical biomarkers and immunotherapeutic strategies that target α-synuclein in neurodegenerative disease

Concentration of an alpha-synuclein standard solution decreases with preincubation.

<p>Incubation of freshly diluted alpha-synuclein at 6 ng/ml in PBS for 3, 18 and 32 h at 37°C decreased ELISA-measured alpha-synuclein levels by 21, 66 and 78%, respectively.</p