Klaus Schott

Osteopontin is elevated in Parkinson's disease and its absence leads to reduced neurodegeneration in the MPTP model.

In the pathogenesis of Parkinsons disease (PD), oxidative and nitrosative stress, apoptosis, mitochondrial dysfunction, and excitotoxicity are involved, i.e., processes in which osteopontin (OPN) may also play a role. We have studied in PD patients serum and cerebrospinal fluid (CSF) concentrations of OPN, its immunohistochemical presence in substantia nigra (SN) and tested in OPN-null mice the impact of this protein on MPTP-induced neurodegeneration. PD was accompanied by increased OPN levels in the body fluids. Higher serum levels were associated with more severe motor symptoms. CSF levels were positively associated with concomitant dementia and negatively associated with dopaminergic treatment. In human SN, OPN was expressed in neurons, in their Lewy bodies and in microglia. Loss of tyrosine-hydroxylase-positive cells in the SN and of dopaminergic fibers in the striatum was reduced 3 weeks after MPTP intoxication in OPN-null mice. These data suggest that OPN is involved in PD-associated neurodegeneration.

Autoantibody reactivity in serum of patients with major depression, schizophrenia and healthy controls

The present study assessed 25 patients with unipolar major depression and 34 patients with schizophrenia along with 50 healthy, non-psychiatric controls for the presence of serum antinuclear (ANA), smooth muscle (SMA), anti-endothelial (AEA), anti-sarcolemma (ASA), thyroid gland (TGA) and parietal cell (PCA) antibodies. In the group of patients with major depression, the frequency of elevated ANA, TGA and PCA was significantly higher than in the control group. In addition, the group of patients with schizophrenia significantly more often showed increased levels of ANA and SMA than the control group of healthy volunteers. When the two psychiatric groups were compared, PCA serum titers in major depression and SMA values in schizophrenia were significantly more frequently elevated, whereas values of AEA and ASA showed no difference. These results point towards the existence of an unspecific (auto) immune disposition or reaction in at least a subgroup of patients with major depression and schizophrenia.

Decreased brain-derived neurotrophic factor (BDNF)- and β -thromboglobulin (β -TG)- blood levels in Alzheimer's disease

Decreased brain-derived neurotrophic factor (BDNF)- and β -thromboglobulin (β -TG)- blood levels in Alzheimers disease -

Autoantibodies to serotonin in serum of patients with psychiatric disorders

Antibodies to serotonin in serum were investigated by ELISA in patients with paranoid schizophrenia (N=27), schizoaffective psychosis (N=38), depression (N=67), Alzheimers disease (N=21), chronic alcoholism (N=43), rheumatoid arthritis (N=25), and multiple sclerosis (N=16), and in healthy volunteers (N=60). Increased antibody reactivity to serotonin was found in schizoaffective psychosis, chronic alcoholism, and rheumatoid arthritis. Decreased antibody reactivity to serotonin was found in multiple sclerosis and depression. These anti-serotonin antibodies belong to the class of so-called natural autoantibodies. Alterations of these natural autoantibodies could indicate a disturbance to the immune system. It is possible that these antibodies could also influence receptor function. Autoantibodies to neurotransmitters in a wide spectrum of psychiatric disorders have not previously been reported.

The use of protease inhibitors in experimental allergic neuritis

In experimental allergic neuritis (EAN) break-down of myelin is attributed to macrophages, which among other factors contain and secrete proteases. In vitro studies have shown that cathepsin D, an acidic aspartyl endopeptidase, and plasmin can degrade myelin proteins. In order to elucidate a potential therapeutic effect of protease inhibitors we treated Lewis rats, immunized with bovine peripheral nervous system myelin, with epsilon-amino-caproic acid (EACA) or pepstatin. EACA or pepstatin was administered twice daily by intraperitoneal injection beginning on day 6 postimmunization or from the onset of disease (on day 12) through day 24. Compared to saline-treated controls, animals treated with either of the inhibitors showed delayed development of clinical signs and electrophysiological abnormalities. Maximal severity and the further course of disease, however, were not different in control and treated groups. Immunohistological evaluation of sciatic nerve specimens on day 24 postimmunization showed equal numbers of cells positive for ED1 (macrophages) and cathepsin D in all animal groups. There was also no difference in the spontaneous proteolytic activity of the sciatic nerve homogenates at pH 2.8, 5.0, and 7.4. Incubation of the homogenates with pepstatin, however, significantly reduced proteolytic activity at pH 2.8 and 5.0, while EACA had no effect at any pH tested. These results imply that treatment to limit the infiltration of cathepsin D-positive cells or to reduce the induction or activity of cathepsin D may provide a therapeutic avenue for treating inflammatory demyelination of the peripheral nervous system.

Diminished Production of Proinflammatory Cytokines in Patients with Alzheimer’s Disease

Cerebral inflammation as well as systemic immunological alterations have been reported in Alzheimer’s disease (AD). We examined the production of the proinflammatory cytokines interleukin-6, interleukin-12, interferon-γ, and tumor necrosis factor-α in whole blood cell cultures of AD patients and age-matched controls. The production of all measured cytokines after mitogen stimulation is significantly decreased in the AD group compared to controls. The results reflect an attenuated secretory activity of monocytes/macrophages, but also of T-helper cells. The data sustain the assumption that a systemic, possibly age-related alteration of immune mechanisms may play a pathogenetic role in the development of AD.

Role of endoneural cells in experimental allergic neuritis and characterisation of a resident phagocytic cell

SummaryElectrophysiological, clinical and histological techniques were used to monitor the time course of events related to experimental allergic neuritis (EAN) in 48 Lewis rats. The primary lesion was found to be paranodal demyelination without cellular infiltration. Endoneural phagocytes derive from hematogenous ED1+ED2− monocytes and possibly from resident ED1− ED2+ monocytic cells, not from Schwann cells and fibroblasts. We demonstrate a population of monocytic Ia-bearing, ED1−ED2+ spindle-shaped cells residing in normal peripheral nerve and provide evidence for their transformation into macrophages in the course of EAN.

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.

Posttranscriptional regulation of the immediate-early gene EGR1 by light in the mouse retina.

Synaptic plasticity is modulated by differential regulation of transcription factors such as EGR1 which binds to DNA via a zinc finger binding domain. Inactivation of EGR1 has implicated this gene as a key regulator of memory formation and learning. However, it remains puzzling how synaptic input can lead to an up‐regulation of the EGR‐1 protein within only a few minutes. Here, we show by immunohistochemical staining that the EGR‐1 protein is localized in synapses throughout the mouse retina. We demonstrate for the first time that two variants of Egr‐1 mRNA are produced in the retina by alternative polyadenylation, with the longer version having an additional 293 base pairs at the end of the 3′UTR. Remarkably, the use of the alternative polyadenylation site is controlled by light. The additional 3′UTR sequence of the longer variant displays an even higher level of phylogenetic conservation than the coding region of this highly conserved gene. Additionally, it harbours a cytoplasmic polyadenylation element which is known to respond to NMDA receptor activation. The longer version of the Egr‐1 mRNA could therefore rapidly respond to excitatory stimuli such as light or glutamate release whereas the short variant, which is predominantly expressed and contains the full coding sequence, lacks the regulatory elements for cytoplasmic polyadenylation in its 3′UTR.

Autoantibody reactivity in serum of patients with alzheimer's disease and other age-related dementias

Serum antibodies against a series of antigens, including an organ-specific central nervous system (CNS) antigen and the neurotransmitter serotonin, were investigated in 22 patients with Alzheimers Disease (n=15) and other age-related dementias (n=7) by indirect immunofluorescence assay and enzyme-linked immunosorbent assay. Patients with dementia showed an increase of antibody-positive sera against nuclear antigen, gastric parietal cells, CNS antigen, gangliosides (Gm1), laminin, and keratin. Alzheimers Disease patients alone exhibited antibodies against CNS antigen. However, the results do not show sufficient specificity and sensitivity for use as a diagnostic indicator.