| 1. |
- Abrahamsson, Therése, 1976, et al.
(author)
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Reversible synaptic depression in developing rat CA3-CA1 synapses explained by a novel cycle of AMPA silencing-unsilencing
- 2007
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In: JOURNAL OF NEUROPHYSIOLOGY. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 98:5, s. 2604-2611
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Journal article (peer-reviewed)abstract
- In the developing hippocampus, experiments using whole cell recordings have shown that a small number of synaptic activations can convert many glutamate synapses to AMPA silent synapses. This depression of AMPA signaling is induced by low-frequency (0.05–0.2 Hz) activation, does not require N-methyl-d-aspartate or metabotropic glutamate receptor activation for its induction, and does not readily reverse after stimulus interruption. Here we show, using field recordings and perforated patch-clamp recordings of transmission in developing CA3–CA1 synapses, that this synaptic depression also can be observed under more noninvasive recording conditions. Moreover, under these conditions, the synaptic depression spontaneously recovers within 20 min by the absence of synaptic activation alone, with a time constant of ∼7 min as determined by field excitatory postsynaptic potential recordings. Thus as for the expression of long-term potentiation (LTP), recovery from this depression is susceptible to whole cell dialysis (“wash-out”). In contrast to LTP-induced unsilencing, the AMPA signaling after stimulus interruption was again labile, resumed stimulation resulted in renewed depression. The present study has thus identified a novel cycle for AMPA signaling in which the nascent glutamate synapse cycles between an AMPA silent state, induced by a small number of synaptic activations, and a labile AMPA signaling, induced by prolonged inactivity.
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| 2. |
- Adlerz, Linda, 1974-
(author)
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Processing of the amyloid precursor protein and its paralogues amyloid precursor-like proteins 1 and 2
- 2007
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Doctoral thesis (other academic/artistic)abstract
- Alzheimer’s disease (AD) is a neurodegenerative disorder which is histopathologically characterised by amyloid plaques and neurofibrillary tangles. Amyloid plaques consist of the amyloid β-peptide (Aβ) that can form aggregates in the brain. Aβ is generated from the amyloid precursor protein (APP) through proteolytic cleavage. APP belongs to a conserved protein family that also includes the two paralogues, APP-like proteins 1 and 2 (APLP1 and APLP2). Despite the immense amount of research on APP, motivated by its implication in AD, the function of this protein family has not yet been determined. In this thesis, we have studied the expression and proteolytic processing of the APP protein family. Our results are consistent with previous findings that suggest a role for APP during neuronal development. Treatment of cells with retinoic acid (RA) resulted in increased synthesis. In addition, we observed that RA treatment shifted the processing of APP from the amyloidogenic to the non-amyloidogenic pathway. The proteins in the APP family have been hard to distinguish both with respect to function and proteolytic processing. However, for development of new drugs with APP processing enzymes as targets this is of great importance. Our studies suggest similarities, but also differences in the mechanism regulating the processing of the different paralogues. We found that brain-derived neurotrophic factor (BDNF) had different impact on the members of the APP family. Most interestingly, we also found that the mechanism behind the increased processing in response to IGF-1 was not identical between the homologous proteins. In summary, our results indicate that in terms of regulation APLP1 and APLP2 differ more from each other than from APP. Our studies open up the possibility of finding means to selectively block Aβ production without interfering with the processing and function of the paralogous proteins.
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| 3. |
- Ahuja-Jensen, Poonam, et al.
(author)
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Low glutathione peroxidase in rdl mouse retina increases oxidative stress and proteases
- 2007
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In: NeuroReport. - 1473-558X. ; 18:8, s. 797-801
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Journal article (peer-reviewed)abstract
- Malondialdehyde, reduced glutathione, glutathione peroxidase, glutathione reductase and cysteine protease cathepsins at postnatal (PN) days 2, 7, 14, 21 and 28 in controls (wt) and the retinal degeneration 1 (rd1) mouse model for retinitis pigmentosa retinas were measured to determine oxidative stress. In PN28 wt and PN2 rd1 retinas, elevated malondialdehyde and low glutathione peroxidase activity indicate higher oxidative load, despite higher reduced glutathione in PN2 rd1 retinas. This is due to physiological exposure to light and retinal vascular/neural restructuring, respectively. Compared with wt retinas, relatively high malondialdehyde at PN2 and cathepsin levels at PN14, 21 and 28 in rd1 retinas indicate that cells of the residual inner retina also contribute to the oxidative stress and retinal degeneration.
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| 4. |
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| 5. |
- Andersson, Christin, et al.
(author)
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Differential CSF biomarker levels in APOE-epsilon4-positive and -negative patients with memory impairment.
- 2007
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In: Dementia and geriatric cognitive disorders. - Basel : S. Karger AG. - 1420-8008 .- 1421-9824. ; 23:2, s. 87-95
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To investigate the relationships between episodic memory, APOE genotype, CSF markers (total tau, T-tau; phospho-tau, P-tau; beta-amyloid, Abeta42) and longitudinal cognitive decline. METHODS: 124 memory clinic patients were retrospectively divided into 6 groups based on (i) episodic memory function (Rey Auditory Verbal Learning Test, RAVLT): severe, moderate or no impairment (SIM, MIM or NIM), and (ii) APOE genotype (epsilon4+ or epsilon4-). CSF marker levels and cognitive decline were compared across groups. RESULTS: Episodic memory function, according to RAVLT scores, was significantly correlated with CSF marker levels only among epsilon4+ subjects and not among epsilon4- subjects. When comparing the 6 subgroups, SIM epsilon4+ and MIM epsilon4+ groups showed significantly lower Abeta42 levels than the other groups. T-tau and P-tau levels were significantly increased in SIM epsilon4+ when compared to all the other groups, including the SIM epsilon4- group. However, both SIM epsilon4+ and SIM epsilon4- declined cognitively during the follow-up. CONCLUSION: It remains to be determined whether APOE genotype affects the expression of biomarkers in CSF, or whether the different biomarker patterns reflect different types of disease processes in patients with progressive cognitive dysfunction.
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| 6. |
- Andersson, Elin, et al.
(author)
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Ngn2 and Nurr1 act in synergy to induce midbrain dopaminergic neurons from expanded neural stem and progenitor cells.
- 2007
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In: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 313:6, s. 1172-1180
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Journal article (peer-reviewed)abstract
- Parkinson's Disease (PD) is a debilitating motor function disorder due primarily to a loss of midbrain dopaminergic neurons and a subsequent reduction in dopaminergic innervation of the striatum. Several attempts have been made to generate dopaminergic neurons from progenitor cell populations in vitro for potential use in cell replacement therapy for PD. However, expanding cells from fetal brain with retained potential for dopaminergic differentiation has proven to be difficult. In this study, we sought to generate mesencephalic dopaminergic (mesDA) neurons from an expanded population of fetal mouse ventral midbrain (VM) progenitors through the use of retroviral gene delivery. We over-expressed Ngn2 and Nurr1, two genes present in the ventral midbrain and important for normal development of mesDA neurons, in multipassaged neurosphere-expanded midbrain progenitors. We show that over-expression of Ngn2 in these progenitors results in increased neuronal differentiation but does not promote mesDA formation. We also show that over-expression of Nurr1 alone is sufficient to generate tyrosine hydroxylase (TH) expressing cells with an immature morphology, however the cells do not express any additional markers of mesDA neurons. Overexpression of Nurr1 and Ngn2 in combination generates morphologically mature TH-expressing neurons that also express additional mesencephalic markers. (c) 2006 Elsevier Inc. All rights reserved.
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| 7. |
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| 8. |
- Araujo, I. M., et al.
(author)
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Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons
- 2007
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In: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 14:9, s. 1635-1646
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Journal article (peer-reviewed)abstract
- Proteolytic cleavage of the Na+/Ca2+ exchanger (NCX) by calpains impairs calcium homeostasis, leading to a delayed calcium overload and excitotoxic cell death. However, it is not known whether reversal of the exchanger contributes to activate calpains and trigger neuronal death. We investigated the role of the reversal of the NCX in Ca2+ dynamics, calpain activation and cell viability, in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-stimulated hippocampal neurons. Selective overactivation of AMPA receptors caused the reversal of the NCX, which accounted for approximately 30% of the rise in intracellular free calcium concentration ([Ca2+](i)). The NCX reverse-mode inhibitor, 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl] isothiourea (KB-R7943), partially inhibited the initial increase in [Ca2+](i), and prevented a delayed increase in [Ca2+](i). In parallel, overactivation of AMPA receptors strongly activated calpains and led to the proteolysis of NCX3. KB-R7943 prevented calpain activation, cleavage of NCX3 and was neuroprotective. Silencing of NCX3 reduced Ca2+ uptake, calpain activation and was neuroprotective. Our data show for the first time that NCX reversal is an early event following AMPA receptor stimulation and is linked to the activation of calpains. Since calpain activation subsequently inactivates NCX, causing a secondary Ca2+ entry, NCX may be viewed as a new suicide substrate operating in a Ca2+-dependent loop that triggers cell death and as a target for neuroprotection.
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| 9. |
- Archer, Trevor, 1949, et al.
(author)
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Behavioural supersensitivity following neonatal 6-hydroxydopamine : Attenuation by MK-801
- 2007
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In: Neurotoxicity research. - 1029-8428 .- 1476-3524. ; 12:2, s. 113-124
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Journal article (peer-reviewed)abstract
- Male rat pups were administered 6-hydroxydopamine (6-OHDA, 75 μg, intracisternally, 30 min after desipramine, 25 mg/kg, s.c.) on Days 1 or 2 after birth, or were sham-operated (receiving vehicle). In four experiments, the acute effects of apomorphine, with or without pretreatment with MK-801 (0.03 mg/kg), upon motor activity in test chambers was measured. Acute treatment with apomorphine (0.1 mg/kg) increased locomotor, rearing and total activity markedly compared to both the acute saline administered 6-OHDA rats and the sham-operated rats administered saline. Acute MK-801 (0.03 mg/kg) co-administered shortly before (5 min) apomorphine (0.3 or 1.0 mg/kg) reduced markedly locomotion and total activity in 6-OHDA-treated and sham-operated rats. Rearing behaviour was increased in both the 6-OHDA groups of rats. Acute MK-801 increased activity in the 6-OHDA-treated rats, which was not observed in sham-operated rats. At the 0.3 and 1.0 mg/kg doses of apomorphine, neonatal 6-OHDA treament increased all three parameters of motor activity. Acute treatment with apomorphine (0.1 mg/kg) induced different effects on the motor activity of 6-OHDA-treated and sham-operated mice. In sham-operated rats apomorphine reduced motor activity during the 1st 30-min period but increased locomotion and total activity, but not rearing, during the 2nd and 3rd periods, whereas in 6-OHDA-treated rats, apomorphine increased locomotor, rearing and total activity markedly. Dopamine loss and serotonin elevation in the striatum and olfactory tubercle were confirmed. The present findings confirm the influence of non-competitive glutamate antagonists in attenuating the behavioural supersensitivity to dopamine antagonists.
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| 10. |
- Archer, Trevor, 1949, et al.
(author)
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Functional consequences of iron overload in catecholaminergic interactions: the Youdim factor
- 2007
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In: Neurochemical Research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 32:10, s. 1625-1639
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Research review (peer-reviewed)abstract
- The influence of postnatal iron overload upon implications of the functional and interactive role of dopaminergic and noradrenergic pathways that contribute to the expressions of movement disorder and psychotic behaviours in mice was studied in a series of experiments. (1) Postnatal iron overload at doses of 7.5 mg/kg (administered on Days 10–12 post partum) and above, invariably induced a behavioural syndrome consisting of an initial (1st 20–40 min of a 60-min test session) hypoactivity followed by a later (final 20 min of a 60-min test session) hyperactivity, when the mice were tested at adult ages (age 60 days or more). (2) Following postnatal iron overload, subchronic treatment with the neuroleptic compounds, clozapine and haloperidol, dose-dependently reversed the initial hypoactivity and later hyperactivity induced by the metal. Furthermore, DA D2 receptor supersensitivity (as assessed using the apomorphine-induced behaviour test) was directly and positively correlated with iron concentrations in the basal ganglia. (3) Brain noradrenaline (NA) denervation, using the selective NA neurotoxin, DSP4, prior to administration of the selective DA neurotoxin, MPTP, exacerbated both the functional (hypokinesia) and neurochemical (DA depletion) effects of the latter neurotoxin. Treatment with L-Dopa restored motor activity only in the animals that had not undergone NA denervation. These findings suggest an essential neonatal iron overload, termed “the Youdim factor”, directing a DA–NA interactive component in co-morbid disorders of nigrostriatal-limbic brain regions.
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