Jana Sirova

N-Methyl-d-Aspartate Receptor – Nitric Oxide Synthase Pathway in the Cortex of Nogo-A-Deficient Rats in Relation to Brain Laterality and Schizophrenia

It has been suggested that Nogo-A, a myelin-associated protein, could play a role in the pathogenesis of schizophrenia and that Nogo-A-deficient rodents could serve as an animal model for schizophrenic symptoms. Since changes in brain laterality are typical of schizophrenia, we investigated whether Nogo-A-deficient rats showed any signs of disturbed asymmetry in cortical N-methyl-d-aspartate (NMDA) receptor–nitric oxide synthase (NOS) pathway, which is reported as dysfunctional in schizophrenia. In particular, we measured separately in the right and left hemisphere of young and old Nogo-A-deficient male rats the expression of NMDA receptor subunits (NR1, NR2A, and NR2B in the frontal cortex) and activities of NOS isoforms [neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) in the parietal cortex]. In young controls, we observed right/left asymmetry of iNOS activity and three positive correlations (between NR1 in the left and NR2B laterality, between NR2B in the right and left sides, and between NR1 in the right side and nNOS laterality). In old controls, we found bilateral decreases in NR1, an increase in NR2B in the right side, and two changes in correlations in the NR1–nNOS pathway. In young Nogo-A-deficient rats, we observed an increase in iNOS activity in the left hemisphere and two changes in correlations in NR1–nNOS and NR2A–eNOS, compared to young controls. Finally, we revealed in old Nogo-A-deficient animals, bilateral decreases in NR1 and one change in correlation between eNOS–iNOS, compared to old controls. Although some findings from schizophrenic brains did not manifest in Nogo-A-deficient rats (e.g., no alterations in NR2B), others did (e.g., alterations demonstrating accelerated aging in young but not old animals, those occurring exclusively in the right hemisphere in young and old animals and those suggesting abnormal frontoparietal cortical interactions in young animals).

Interactions between Amyloid-β and Tau in Cerebrospinal Fluid of People with Mild Cognitive Impairment and Alzheimer's Disease

BACKGROUND Despite the physiological sequestration of amyloid-β (Aβ) peptides by various carriers, interactions between peptides and protein tau appear to be pathological and involved in the development of Alzheimers disease (AD). A recent study reported increased Aβ-tau interactions in the neurons of AD patients. OBJECTIVE We investigated the possibility that levels of Aβ-tau complexes in cerebrospinal fluid could be a prospective biomarker of AD, with greater sensitivity and specificity than Aβ1-42, tau, or phospho-tau individually. METHODS By means of ELISA, we estimated levels of the complexes in 161 people (non-demented controls, people with mild cognitive impairment (MCI), probable AD or other types of dementia). RESULTS We found significant reductions in levels in people with MCI due to AD (down to 84.5%) or with AD (down to 80.5%) but not in other types of dementia. The sensitivity of the new biomarker to AD was 68.6%, the specificity 73.3% (compared to controls) or 59.1-66.1% (compared to other types of dementia). No significant correlations were observed between the complexes and the remaining biomarkers or between those and Mini-Mental State Examination score. CONCLUSION We suppose that attenuated levels of complexes in cerebrospinal fluid reflect the accumulation of Aβ bound to tau in AD neurons and that changes start many years before symptom onset, analogously to those in Aβ1-42, tau, or phospho-tau. Unfortunately, these complexes are not a significantly better biomarker of AD than current biomarkers.

A Rat Model of Alzheimer’s Disease Based on Abeta42 and Pro-oxidative Substances Exhibits Cognitive Deficit and Alterations in Glutamatergic and Cholinergic Neurotransmitter Systems

Alzheimer’s disease (AD) is one of the most serious human, medical, and socioeconomic burdens. Here we tested the hypothesis that a rat model of AD (Samaritan; Taconic Pharmaceuticals, USA) based on the application of amyloid beta42 (Abeta42) and the pro-oxidative substances ferrous sulfate heptahydrate and L-buthionine-(S, R)-sulfoximine, will exhibit cognitive deficits and disruption of the glutamatergic and cholinergic systems in the brain. Behavioral methods included the Morris water maze (MWM; long-term memory version) and the active allothetic place avoidance (AAPA) task (acquisition and reversal), testing spatial memory and different aspects of hippocampal function. Neurochemical methods included testing of the NR1/NR2A/NR2B subunits of NMDA receptors in the frontal cortex and CHT1 transporters in the hippocampus, in both cases in the right and left hemisphere separately. Our results show that Samaritan rats™ exhibit marked impairment in both the MWM and active place avoidance tasks, suggesting a deficit of spatial learning and memory. Moreover, Samaritan rats exhibited significant changes in NR2A expression and CHT1 activity compared to controls rats, mimicking the situation in patients with early stage AD. Taken together, our results corroborate the hypothesis that Samaritan rats are a promising model of AD in its early stages.

Trans-generational neurochemical modulation of methamphetamine in the adult brain of the Wistar rat

Chronic methamphetamine (METH) abuse has been shown to elicit strong neurotoxic effects. Yet, with an increasing number of children born to METH abusing mothers maturing into adulthood, one important question is how far do the neurotoxic effects of METH alter various neurotransmitter systems in the adult METH-exposed offspring. The purpose of this study was to investigate long-term trans-generational neurochemical changes, following prenatal METH exposure, in the adult Wistar rat brain. METH or saline (SAL—control animals) was administered to pregnant dams throughout the entire gestation period (G0-G22). At postnatal day 90, dopamine, serotonin, glutamate and GABA were measured in the adult brain before (baseline) and after a METH re-administration using in vivo microdialysis and liquid chromatography/mass spectrometry. The results show that METH-exposure increased basal levels of monoamines and glutamate, but decreased GABA levels in all measured brain regions. Acute challenge with METH injection in the METH-exposed group induced a lower increase in the monoamine system relative to the increase in the GABAergic and glutamatergic system. The data show that prenatal METH exposure has strong effects on the monoaminergic, GABAergic and glutamatergic system even when exposure to METH was limited to the prenatal phase. Toxicological effects of METH have therefore longer lasting effects as currently considered and seem to affect the excitatory-inhibitory balance in the brain having strong implications for cognitive and behavioral functioning.

Chronic methamphetamine self-administration dysregulates 5-HT2A and mGlu2 receptor expression in the rat prefrontal and perirhinal cortex: Comparison to chronic phencyclidine and MK-801

ABSTRACT Chronic methamphetamine (meth) abuse often turns into a compulsive drug‐taking disorder accompanied by persistent cognitive deficits and re‐occurring psychosis. Possible common neurobiological substrates underlying meth‐induced deficits and schizophrenia remain poorly understood. Serotonin 2A (5‐HT2A) and metabotropic glutamate 2 (mGlu2) receptors co‐regulate psychosis‐like behaviors and cognitive function in animals. Therefore, in the present study we examined the effects of chronic exposure to three different drugs known to produce persistent deficits in sensorimotor gating and cognition [meth, phencyclidine (PCP) and MK‐801] on the expression of 5‐HT2A and mGlu2 within the rat medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC) and perirhinal cortex (PRh). Adult male rats underwent 14days of: (a) meth self‐administration (6h/day), (b) phencyclidine (PCP; 5mg/kg, twice/day) administration, or (c) MK‐801 (0.3mg/kg, twice/day) administration. Seven days after the discontinuation of drug administration, tissues of interest were collected for protein expression analysis. We found that despite different pharmacological mechanism of action, chronic meth, PCP, and MK‐801 similarly dysregulated 5‐HT2A and mGlu2, as indicated by an increase in the 5‐HT2A/mGlu2 expression ratio in the mPFC (all three tested drugs), PRh (meth and PCP), and dHPC (MK‐801 only). Complementary changes in G‐protein expression (increase in G&agr;q and decrease in G&agr;i) were also observed in the mPFC of meth animals. Finally, we found that 5‐HT2A/mGlu2 cooperation can be mediated in part by the formation of the receptor heteromer in some, but not all cortical regions. In summary, these data suggest that a shift towards increased availability (and G‐protein coupling) of cortical 5‐HT2A vs. mGlu2 receptors may represent a common neurobiological mechanism underlying the emergence of psychosis and cognitive deficits observed in subjects with meth use disorder and schizophrenia. HIGHLIGHTS5‐HT2A and mGlu2 receptors co‐immunoprecipitate in the rat cortical tissue.Chronic meth increased the 5‐HT2A/mGlu2 expression ratio in the mPFC and PRh.Chronic PCP and MK‐801 also increased the 5‐HT2A/mGlu2 expression ratio in the mPFC.Chronic meth increased 5‐HT2A partner G‐protein (G&agr;q) in the mPFC.

Levels of 17β-Hydroxysteroid Dehydrogenase Type 10 in Cerebrospinal Fluid of People with Mild Cognitive Impairment and Various Types of Dementias

BACKGROUND Overexpression of the mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10, which is also known as the intracellular amyloid-β peptide (Aβ) binding protein) is observed in cortical or hippocampal regions of patients with Alzheimers disease (AD). It appears that 17β-HSD10 may play a role in the pathogenesis of AD. OBJECTIVE We investigated the possibility that levels of 17β-HSD10 in cerebrospinal fluid could be a prospective biomarker of AD. METHODS We estimated the enzyme levels in 161 people (15 non-demented controls, 52 people with mild cognitive impairment (MCI), 35 people with probable AD, or 59 people with other types of dementia) and compared them with those of Aβ(1- 42), tau, and phospho-tau. RESULTS We found significantly higher levels of 17β-HSD10 in people with MCI due to AD (to 109.9% ), with AD (to 120.0% ), or with other types of dementia (to 110.9% ) when compared to the control group. The sensitivity of the new biomarker to AD was 80.0% , and the specificity was 73.3% (compared to controls) or 52.5-59.1% (compared to other types of dementia). Results of multiple linear regression and of correlation analysis revealed AD-mediated changes in links between 17β-HSD10 and Mini Mental State Examination score. CONCLUSION It seems that changes in 17β-HSD10 start many years before symptom onset, analogous to those in Aβ1 - 42, tau, or phospho-tau and that the levels are a relatively highly sensitive but unfortunately less specific biomarker of AD. A role of 17β-HSD10 overexpression in AD is discussed.