Alejandra Rangel

Enhanced susceptibility of Prnp-deficient mice to kainate-induced seizures, neuronal apoptosis, and death: Role of AMPA/kainate receptors

Normal physiologic functions of the cellular prion protein (PrPc) are still elusive. This GPI‐anchored protein exerts many functions, including roles in neuron proliferation, neuroprotection or redox homeostasis. There are, however, conflicting data concerning its role in synaptic transmission. Although several studies report that PrPc participates in NMDA‐mediated neurotransmission, parallel studies describe normal behavior of PrPc‐mutant mice. Abnormal axon connections have been described in the dentate gyrus of the hippocampi of PrPc‐deficient mice similar to those observed in epilepsy. A study indicates increased susceptibility to kainate (KA) in these mutant mice. We extend the observation of these studies by means of several histologic and biochemical analyses of KA‐treated mice. PrPc‐deficient mice showed increased sensitivity to KA‐induced seizures in vivo and in vitro in organotypic slices. In addition, we show that this sensitivity is cell‐specific because interference experiments to abolish PrPc expression increased susceptibility to KA in PrPc‐expressing cells. We indicate a correlation of susceptibility to KA in cells lacking PrPc with the differential expression of GluR6 and GluR7 KA receptor subunits using real‐time RT‐PCR methods. These results indicate that PrPc exerts a neuroprotective role against KA‐induced neurotoxicity, probably by regulating the expression of KA receptor subunits.

Regulation of GABAA and Glutamate Receptor Expression, Synaptic Facilitation and Long-Term Potentiation in the Hippocampus of Prion Mutant Mice

Background Prionopathies are characterized by spongiform brain degeneration, myoclonia, dementia, and periodic electroencephalographic (EEG) disturbances. The hallmark of prioniopathies is the presence of an abnormal conformational isoform (PrPsc) of the natural cellular prion protein (PrPc) encoded by the Prnp gene. Although several roles have been attributed to PrPc, its putative functions in neuronal excitability are unknown. Although early studies of the behavior of Prnp knockout mice described minor changes, later studies report altered behavior. To date, most functional PrPc studies on synaptic plasticity have been performed in vitro. To our knowledge, only one electrophysiological study has been performed in vivo in anesthetized mice, by Curtis and coworkers. They reported no significant differences in paired-pulse facilitation or LTP in the CA1 region after Schaffer collateral/commissural pathway stimulation. Methodology/Principal Findings Here we explore the role of PrPc expression in neurotransmission and neural excitability using wild-type, Prnp −/− and PrPc-overexpressing mice (Tg20 strain). By correlating histopathology with electrophysiology in living behaving mice, we demonstrate that both Prnp −/− mice but, more relevantly Tg20 mice show increased susceptibility to KA, leading to significant cell death in the hippocampus. This finding correlates with enhanced synaptic facilitation in paired-pulse experiments and hippocampal LTP in living behaving mutant mice. Gene expression profiling using Illumina™ microarrays and Ingenuity pathways analysis showed that 129 genes involved in canonical pathways such as Ubiquitination or Neurotransmission were co-regulated in Prnp −/− and Tg20 mice. Lastly, RT-qPCR of neurotransmission-related genes indicated that subunits of GABAA and AMPA-kainate receptors are co-regulated in both Prnp −/− and Tg20 mice. Conclusions/Significance Present results demonstrate that PrPc is necessary for the proper homeostatic functioning of hippocampal circuits, because of its relationships with GABAA and AMPA-Kainate neurotransmission. New PrPc functions have recently been described, which point to PrPc as a target for putative therapies in Alzheimers disease. However, our results indicate that a “gain of function” strategy in Alzheimers disease, or a “loss of function” in prionopathies, may impair PrPc function, with devastating effects. In conclusion, we believe that present data should be taken into account in the development of future therapies.

Chronic Neuroinflammation in Alzheimer’s Disease: New Perspectives on Animal Models and Promising Candidate Drugs

Chronic neuroinflammation is now considered one of the major factors in the pathogenesis of Alzheimers disease (AD). However, the most widely used transgenic AD models (overexpressing mutated forms of amyloid precursor protein, presenilin, and/or tau) do not demonstrate the degree of inflammation, neurodegeneration (particularly of the cholinergic system), and cognitive decline that is comparable with the human disease. Hence a more suitable animal model is needed to more closely mimic the resulting cognitive decline and memory loss in humans in order to investigate the effects of neuroinflammation on neurodegeneration. One of these models is the glial fibrillary acidic protein-interleukin 6 (GFAP-IL6) mouse, in which chronic neuroinflammation triggered constitutive expression of the cytokine interleukin-6 (IL-6) in astrocytes. These transgenic mice show substantial and progressive neurodegeneration as well as a decline in motor skills and cognitive function, starting from 6 months of age. This animal model could serve as an excellent tool for drug discovery and validation in vivo. In this review, we have also selected three potential anti-inflammatory drugs, curcumin, apigenin, and tenilsetam, as candidate drugs, which could be tested in this model.

Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7–PSD-95 binding

Cellular prion protein neuroprotection against kainate is due to its ability to modulate glutamate receptor 6/7–mediated neurotransmission and JNK3 pathway activation.

Anxiolysis followed by anxiogenesis relates to coping and corticosterone after medial prefrontal cortical damage in rats

Medial prefrontal cortex (MPFC) damage causes profound behavioral and neuroendocrine alterations. However, many reports have been inconsistent regarding the direction of these effects. We hypothesized that the lesion recovery stage might be a key factor generating discrepancies. To examine changes over time following ibotenic acid lesion in the ventral part of the MPFC, behavioral and endocrine testing was conducted on the second and the fifth week after lesioning. On the second post-lesion week, bilaterally lesioned animals increased social interaction and swimming scores and their corticosterone response to restraint was exaggerated as compared with shams. On the fifth post-lesion week, social interaction and swimming scores were diminished in bilaterally lesioned animals; their basal plasma corticosterone was enhanced, while their corticosterone increase under restraint was blunted relative to shams. These results reveal that the emotional and endocrine responses to stress vary as a function of time following MPFC lesion, which may help to reconcile conflicting reports on effect direction. The role of the MPFC in anxiety, ability to cope with stress and adrenal regulation is also discussed.

Distinct patterns of spread of prion infection in brains of mice expressing anchorless or anchored forms of prion protein

BackgroundIn humans and animals, prion protein (PrP) is usually expressed as a glycophosphatidylinositol (GPI)-anchored membrane protein, but anchorless PrP may be pathogenic in humans with certain familial prion diseases. Anchored PrP expressed on neurons mediates spread of prions along axons in the peripheral and central nervous systems. However, the mechanism of prion spread in individuals expressing anchorless PrP is poorly understood. Here we studied prion spread within brain of mice expressing anchorless or anchored PrP.ResultsTo create a localized initial point of infection, we microinjected scrapie in a 0.5 microliter volume in the striatum. In this experiment, PrPres and gliosis were first detected in both types of mice at 40 days post-inoculation near the needle track. In mice with anchored PrP, PrPres appeared to spread via neurons to distant connected brain areas by the clinical endpoint at 150 days post-inoculation. This PrPres was rarely associated with blood vessels. In contrast, in mice with anchorless PrP, PrPres spread did not follow neuronal circuitry, but instead followed a novel slower pattern utilizing the drainage system of the brain interstitial fluid (ISF) including perivascular areas adjacent to blood vessels, subependymal areas and spaces between axons in white matter tracts.ConclusionsIn transgenic mice expressing anchorless PrP small amyloid-seeding PrPres aggregates appeared to be transported in the ISF, thus spreading development of cerebral amyloid angiopathy (CAA) throughout the brain. Spread of amyloid seeding by ISF may also occur in multiple human brain diseases involving CAA.

Neurites regrowth of cortical neurons by GSK3β inhibition independently of Nogo receptor 1

J. Neurochem. (2010) 113, 1644–1658.

High bioavailability curcumin: an anti-inflammatory and neurosupportive bioactive nutrient for neurodegenerative diseases characterized by chronic neuroinflammation

Neuroinflammation is a pathophysiological process present in a number of neurodegenerative disorders, such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, stroke, traumatic brain injury including chronic traumatic encephalopathy and other age-related CNS disorders. Although there is still much debate about the initial trigger for some of these neurodegenerative disorders, during the progression of disease, broad range anti-inflammatory drugs including cytokine suppressive anti-inflammatory drugs (CSAIDs) might be promising therapeutic options to limit neuroinflammation and improve the clinical outcome. One of the most promising CSAIDs is curcumin, which modulates the activity of several transcription factors (e.g., STAT, NF-κB, AP-1) and their pro-inflammatory molecular signaling pathways. However, normal curcumin preparations demonstrate low bioavailability in vivo. To increase bioavailability, preparations of high bioavailability curcumin have been introduced to achieve therapeutically relevant concentrations in target tissues. This literature review aims to summarize the pharmacokinetic and toxicity profile of different curcumin formulations.

Lack of influence of prion protein gene expression on kainate-induced seizures in mice: studies using congenic, coisogenic and transgenic strains.

Prion protein (PrP) is a glycosylphosphatidylinositol (GPI) anchored cell surface protein expressed by many cells, including those of the mammalian nervous system. At present the physiologic functions of PrP remain unclear. Deletion of Prnp, the gene encoding PrP in mice, has been shown to alter normal synaptic and electrophysiologic activities, indicating a potential role in seizure susceptibility. However, published efforts to link PrP with seizures, using both in vivo and in vitro models, are conflicting and difficult to interpret due to use of various mouse backgrounds and seizure induction techniques. Here we investigated the role of PrP in kainic acid (KA)-induced seizure sensitivity, using three types of mice. In contrast to previous published results, Prnp-/- mice on the C57BL/10SnJ background had a significant decrease in KA-induced seizure susceptibility. In genetic complementation experiments using a PrP-expressing transgene, genes derived from strain 129/Ola, which flanked the Prnp-/- locus in C57BL/10SnJ mice, rather than Prnp itself, appeared to account for this effect. Furthermore, using coisogenic 129/Ola mice differing only at Prnp, this difference was not reproduced when comparing PrP-negative and PrP-positive mice. In contrast, substrains of PrP-expressing C57BL mice, showed large variations in KA-induced seizure sensitivity. The magnitude of these differences in susceptibility was larger than that associated with the presence of the Prnp gene, suggesting extensive influence of genes other than Prnp on seizure sensitivity in this system.

Tonic and phasic alteration in amygdala 5-HT, glutamate and GABA transmission after prefrontal cortex damage in rats

The relationship between the ventromedial prefrontal cortex and the amygdala during the presentation of an unconditioned fear stimulus was assessed. Rats underwent bilateral ibotenic acid or vehicle administration into the ventromedial prefrontal cortex. Five weeks later, the behavior as well as the neurochemical changes in the amygdala was evaluated before and after a brief cat presentation. Lesioned animal freezing behavior increased 10 times when compared to controls. In the right basolateral amygdala, basal concentrations of 5-HT, 5-HIAA, glutamate and serine were elevated but basal level of GABA was diminished in lesioned animals relative to controls. Sham but not lesioned animals increased 5-HT and decreased GABA and serine levels after cat presentation. Phasic changes in glutamate were not detected either in lesioned or shams but the difference in amygdala glutamate between lesioned and shams persisted after cat presentation. These data show that increased serotonin and glutamate tone and decreased gabaergic tone in the amygdala correlate to elevated fear and anxiety after prefrontal cortex ibotenic acid lesion. The lesion also seems to produce a failure of adaptive changes in neurotransmitter systems revealing lost of control of the ventromedial prefrontal cortex over the amygdala in frightening situations.