| 1. |
- Lindholm, Paivi, et al.
(författare)
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MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain
- 2008
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Ingår i: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431. ; 39:3, s. 356-371
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Tidskriftsartikel (refereegranskat)abstract
- The mesencephalic astrocyte-derived neurotrophic factor (MANF) has been described as a Survival factor for dopaminergic neurons in vitro, but its expression in mammalian tissues is poorly known. MANF and a homologous Protein, the conserved dopamine neurotrophic factor (CDNF), form a novel evolutionary conserved family of neurotrophic factors. Here we used in situ hybridization and immunohistochemistry to characterize MANF expression in developing and adult mouse. MANF expression was widespread in the nervous system and non-neuronal tissues. In the brain, relatively high MANF levels were detected in the cerebral cortex, hippocampus and cerebellar Purkinje cells. After status epilepticus, Manf mRNA expression was transiently increased in the dentate granule cell layer of hippocampus, thalamic reticular nucleus and in several cortical areas. In contrast, following global forebrain ischemia changes in Manf expression were widespread in the hippocampal formation and more restricted in cerebral cortex. The widespread expression of MANF together with its evolutionary conserved nature and regulation by brain insults suggest that it has important functions both under normal and pathological conditions in many tissue types. (C) 2008 Elsevier Inc. All rights reserved.
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| 2. |
- Lindvall, O, et al.
(författare)
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Cell therapy and transplantation in Parkinson's disease
- 2001
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Ingår i: Clinical Chemistry and Laboratory Medicine. - : De Gruyter. - 1434-6621 .- 1437-4331. ; 39:4, s. 356-361
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Tidskriftsartikel (refereegranskat)abstract
- Transplanted human fetal dopamine neurons can reinnervate the striatum in patients with Parkinson's disease (PD). Recent findings using positron emission tomography indicate that the grafts are functionally integrated and restore dopamine release in the patient's striatum. The grafts can exhibit long-term survival without immunological rejection and despite an ongoing disease process and continuous antiparkinsonian drug treatment. In the most successful cases, patients have been able to withdraw L-dopa treatment after transplantation and resume an independent life. About two-thirds of grafted patients have shown clinically useful, partial recovery of motor function. The major obstacle for the further development of this cell replacement strategy is that large amounts of human fetal mesencephalic tissue are needed for therapeutic effects. Stem cells hold promise as a virtually unlimited source of self-renewing progenitors for transplantation. The possibility to generate dopamine neurons from such cells is now being explored using different approaches. However, so far the generated neurons have survived poorly after transplantation in animals.
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| 3. |
- Ahlenius, Henrik, et al.
(författare)
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Adaptor Protein LNK Is a Negative Regulator of Brain Neural Stem Cell Proliferation after Stroke.
- 2012
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Ingår i: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 32:15, s. 5151-5164
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Tidskriftsartikel (refereegranskat)abstract
- Ischemic stroke causes transient increase of neural stem and progenitor cell (NSPC) proliferation in the subventricular zone (SVZ), and migration of newly formed neuroblasts toward the damaged area where they mature to striatal neurons. The molecular mechanisms regulating this plastic response, probably involved in structural reorganization and functional recovery, are poorly understood. The adaptor protein LNK suppresses hematopoietic stem cell self-renewal, but its presence and role in the brain are poorly understood. Here we demonstrate that LNK is expressed in NSPCs in the adult mouse and human SVZ. Lnk(-/-) mice exhibited increased NSPC proliferation after stroke, but not in intact brain or following status epilepticus. Deletion of Lnk caused increased NSPC proliferation while overexpression decreased mitotic activity of these cells in vitro. We found that Lnk expression after stroke increased in SVZ through the transcription factors STAT1/3. LNK attenuated insulin-like growth factor 1 signaling by inhibition of AKT phosphorylation, resulting in reduced NSPC proliferation. Our findings identify LNK as a stroke-specific, endogenous negative regulator of NSPC proliferation, and suggest that LNK signaling is a novel mechanism influencing plastic responses in postischemic brain.
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| 4. |
- Ahlenius, Henrik, et al.
(författare)
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Neural stem and progenitor cells retain their potential for proliferation and differentiation into functional neurons despite lower number in aged brain.
- 2009
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Ingår i: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 29:14, s. 4408-4419
-
Tidskriftsartikel (refereegranskat)abstract
- Neurogenesis in the subventricular zone (SVZ), which gives rise to new neurons in the olfactory bulb, continues throughout life but declines with increasing age. Little is known about how aging affects the intrinsic properties of the neural stem and progenitor cells (NSCs) in SVZ and the functional characteristics of their neuronal progeny. Here, we have compared the properties of NSCs isolated from embryonic lateral ganglionic eminence and adult and aged SVZ in mice using in vivo and in vitro systems, analyzed their gene expression profile, and studied their electrophysiological characteristics before and after differentiation into neurons. We show a loss of NSCs in SVZ from aged mice accompanied by reduced expression of genes for NSC markers, developmentally important transcription factors, and neurogenic factors. However, when isolated in vitro, the NSCs from SVZ of aged animals have capacity for proliferation and multilineage differentiation, including production of functional neurons, similar to that of NSCs in adult mice, albeit with lower efficacy. These properties are of major importance when considering therapeutic applications of neuronal replacement from endogenous NSCs in the injured, aged brain.
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| 5. |
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| 6. |
- Ajmone-Cat, Maria Antonietta, et al.
(författare)
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Prostaglandin E(2) and BDNF levels in rat hippocampus are negatively correlated with status epilepticus severity: No impact on survival of seizure-generated neurons.
- 2006
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 23:1, s. 23-35
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Tidskriftsartikel (refereegranskat)abstract
- Partial and generalized status epilepticus (pSE and gSE) trigger the same level of progenitor cell proliferation in adult dentate gyrus, but survival of new neurons is poor after gSE. Here, we show markedly elevated levels of prostaglandin E-2 (PGE(2)) and brain-derived neurotrophic factor (BDNF) in rat hippocampal formation at 7 days following pSE but not gSE. Administration of the cyclooxygenase (COX) inhibitor flurbiprofen for 1 week, starting at day 8 post-SE, abated PGE(2) and decreased BDNF levels, but did not affect survival of new neurons a weeks later. Thus, high PGE(2) and BDNF levels induced by pSE are probably not of major importance for survival of new neurons during the first days after formation. We propose that they modulate other aspects of synaptic and cellular plasticity, and thereby may influence epileptogenesis.
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| 7. |
- Aked, Joseph, et al.
(författare)
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Attitudes to Stem Cell Therapy among Ischemic Stroke Survivors in the Lund Stroke Recovery Study
- 2017
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Ingår i: Stem Cells and Development. - : Mary Ann Liebert Inc. - 1547-3287 .- 1557-8534. ; 26:8, s. 566-572
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical studies suggest that stem cell therapy (SCT) may improve poststroke recovery, and clinical trials investigating safety are ongoing. However, knowledge about patients' attitudes to SCT in stroke is limited. We evaluated the knowledge and attitudes to this therapeutic approach as well as possible factors influencing this among stroke patients potentially suitable for SCT. Consecutive first-ever acute ischemic stroke patients aged 20-75 years with NIH stroke scale scores 1-18 were included. Exclusion criteria were severe comorbidities or infratentorial stroke. Clinical follow-up after 3-5 years assessed severity of residual stroke symptoms, cognitive function, functional status, patient-reported outcome, and comorbidity, and after receiving standardized information, the participants also completed an eight-item questionnaire on knowledge and attitudes about SCT. The relationships between clinical variables and positive attitude to SCT were assessed with logistic regression analyses. Of 108 patients included at baseline, 84 participated at follow-up and completed the questionnaire. In total, 12% had prior knowledge of SCT. When informed, 63% were positive toward it and 36% reported willingness to participate in SCT trials. Only 5%-8% expressed ethical considerations regarding different stem cell sources. Positive attitudes to SCT were associated with male gender (OR: 3.74; 95% CI: 1.45-9.61; P < 0.01) and better patient-reported outcome (OR: 1.02; 95% CI: 1.00-1.04; P < 0.05). In conclusion, stroke patients had limited prior knowledge of SCT, yet attitudes were positive among the majority after receiving standardized and neutral information. Gender and degree of stroke recovery may influence attitudes to SCT, indicating a need for targeted information to improve knowledge about SCT.
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| 8. |
- Andsberg, Gunnar, et al.
(författare)
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Neuropathological and behavioral consequences of adeno-associated viral vector-mediated continuous intrastriatal neurotrophin delivery in a focal ischemia model in rats.
- 2002
-
Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 9:2, s. 187-204
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Tidskriftsartikel (refereegranskat)abstract
- Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were continuously delivered to the striatum at biologically active levels via recombinant adeno-associated viral (rAAV) gene transfer 4-5 weeks prior to 30 min of middle cerebral artery occlusion (MCAO). The magnitude of the deficits in a battery of behavioral tests designed to assess striatal function was highly correlated to the extent of ischemic damage determined by unbiased stereological estimations of striatal neuron numbers. The delivery of neurotrophins lead to mild functional improvements in the ischemia-induced motor impairments assessed 3-5 weeks after the insult, in agreement with a small but significant increase of the survival of dorsolateral striatal neurons. Detailed phenotypic analysis demonstrated that the parvalbumin-containing interneurons were spared to a greater extent by the neurotrophin treatment as compared to the projection neurons, which agreed with the specificity for interneuron transduction by the rAAV vector. These data show the advantage of the never previously performed combination of precise quantification of the ischemia-induced neuropathology along with detailed behavioural analysis for assessing neuroprotection after stroke. We observe that intrastriatal delivery of NGF and BDNF using a viral vector system can mitigate, albeit only moderately, neuronal death following stroke, which leads to detectable functional sparing. (c)2002 Elsevier Science (USA).
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| 9. |
- Andsberg, Gunnar, et al.
(författare)
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Upregulation of p75 neurotrophin receptor after stroke in mice does not contribute to differential vulnerability of striatal neurons
- 2001
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 169:2, s. 351-363
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Tidskriftsartikel (refereegranskat)abstract
- The survival of different neuron types and the expression of the p75 neurotrophin receptor (p75(NTR)) after focal cerebral ischemia were studied in the mouse striatum using immunocytochemical and histochemical techniques and stereological procedures. As assessed at 1 week after 30 min of middle cerebral artery occlusion, the order of vulnerability was projection neurons > parvalbumin-expressing interneurons > nitric oxide synthase-containing interneurons > cholinergic interneurons. Within the ischemic lesion, projection neurons were almost completely lost whereas cholinergic interneurons were spared. Calretinin-immunoreactive interneurons also seemed resistant to the insult. Expression of p75(NTR) was induced in cholinergic interneurons within the lesioned area, raising the possibility of a protective action. However, the number of cholinergic interneurons was unaffected in p75(NTR) knockout mice subjected to the same ischemic insult. These quantitative data demonstrate that striatal neurons in the mouse are differentially susceptible to ischemic damage and argue against a significant role of p75(NTR) for the high resistance of cholinergic interneurons.
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| 10. |
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| 11. |
- Arvidsson, Andreas, et al.
(författare)
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N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke
- 2001
-
Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 14:1, s. 10-18
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Tidskriftsartikel (refereegranskat)abstract
- Neurogenesis in the adult rat dentate gyrus was studied following focal ischemic insults produced by middle cerebral artery occlusion (MCAO). Animals were subjected to either 30 min of MCAO, which causes damage confined to the striatum, or 2 h of MCAO, which leads to both striatal and cortical infarction. When compared to sham-operated rats, MCAO-rats showed a marked increase of the number of cells double-labelled for 5-bromo-2'-deoxyuridine-5'-monophosphate (BrdU; injected during 4-6 days postischemia) and neuronal-specific antigen (NeuN; a marker of postmitotic neurons) in the ipsilateral dentate granule cell layer and subgranular zone at 5 weeks following the 2 h insult. Only a modest and variable increase of BrdU-labelled cells was found after 30 min of MCAO. The enhanced neurogenesis was not dependent on cell death in the hippocampus, and its magnitude was not correlated to the degree of cortical damage. Systemic administration of the N-methyl-D-aspartate (NMDA) receptor blocker dizocilpine maleate (MK-801) completely suppressed the elevated neurogenesis following 2 h of MCAO. Our findings indicate that stroke leads to increased neurogenesis in the adult rat dentate gyrus through glutamatergic mechanisms acting on NMDA receptors. This modulatory effect may be mediated through changes in the levels of several growth factors, which occur after stroke, and could influence various regulatory steps of neurogenesis.
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| 12. |
- Arvidsson, Andreas, et al.
(författare)
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Neuronal replacement from endogenous precursors in the adult brain after stroke.
- 2002
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 8:9, s. 963-970
-
Tidskriftsartikel (refereegranskat)abstract
- In the adult brain, new neurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknown whether these neurons can replace those lost following damage or disease. Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans.
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| 13. |
- Arvidsson, Andreas, et al.
(författare)
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Stroke induces widespread changes of gene expression for glial cell line-derived neurotrophic factor family receptors in the adult rat brain
- 2001
-
Ingår i: Neuroscience. - 1873-7544. ; 106:1, s. 27-41
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression for glial cell line-derived neurotrophic factor (GDNF) family ligands and receptors was analyzed with in situ hybridization after two focal ischemic insults of different severities. Focal ischemia was induced in rats by either 30 min or 2 h of middle cerebral artery occlusion (MCAO), causing damage to the striatum only, or involving also the parietal cortex, respectively. We found modest, transient elevation of GDNF mRNA in the dentate granule cell layer. In addition, the number of GDNF mRNA-expressing cells increased in the cortex and striatum after 2 h or 30 min of MCAO, respectively. No changes of neurturin or persephin mRNA expression were detected. Both c-Ret and GFRalpha1 mRNA levels were markedly increased in the ipsilateral cortex outside the ischemic lesion at 6-24 h after the 2-h insult, whereas GFRalpha2 expression was decreased in cortical areas both within and outside the lesion. Similar increases of c-Ret and GFRalpha1 mRNA levels were detected in the striatum, and to a lesser extent, in the cortex following 30 min of MCAO. The 2-h insult also gave rise to transient increases of c-Ret and GFRalpha1 mRNA in hippocampal subregions. Thirty minutes and 2 h of MCAO lead to elevated c-Ret, and GFRalpha1 or GFRalpha2 mRNA expression, respectively, in the ipsilateral ventroposterolateral thalamic nucleus. Both insults induced increased levels of GFRalpha1 mRNA in the subventricular zone of the lateral ventricle.Our data indicate major changes of GDNF family signaling in the forebrain, regulated mainly through altered receptor levels, in the post-ischemic phase. These changes could enhance neuroprotective and neuroregenerative responses both to endogenous and exogenous GDNF ligands.
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| 14. |
- Barker, Roger A., et al.
(författare)
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Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease
- 2019
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 25, s. 1045-1053
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Tidskriftsartikel (refereegranskat)abstract
- Clinical studies of Parkinson’s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO (NCT01898390), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials.
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| 15. |
- Barker, Roger A., et al.
(författare)
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The need for a standard for informed consent for collection of human fetal material
- 2022
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 17:6, s. 1245-1247
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Tidskriftsartikel (refereegranskat)abstract
- The ISSCR has developed the Informed Consent Standards for Human Fetal Tissue Donation and Research to promote uniformity and transparency in tissue donation and collection. This standard is designed to assist those working with and overseeing the regulation of such tissue and reassure the wider community and public.
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| 16. |
- Bengzon, Johan, et al.
(författare)
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Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures
- 1997
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Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 94:19, s. 10432-10437
-
Tidskriftsartikel (refereegranskat)abstract
- Neuronal apoptosis was observed in the rat dentate gyrus in two experimental models of human limbic epilepsy. Five hours after one hippocampal kindling stimulation, a marked increase of in situ terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) of fragmented DNA was observed in nuclei located within and on the hilar border of the granule cell layer and in the polymorphic region. Forty kindling stimulations with 5-min interval produced higher numbers of labeled nuclei compared with one stimulation. The increase of TUNEL-positive nuclei was prevented by the protein synthesis inhibitor cycloheximide but not affected by the N-methyl-D-aspartate receptor antagonist MK-801. Kainic acid-induced seizures lead to a pattern of labeling in the hippocampal formation identical to that evoked by kindling. A large proportion of cells displaying TUNEL-positive nuclei was double-labeled by the neuron-specific antigen NeuN, demonstrating the neuronal identity of apoptotic cells. Either 1 or 40 kindling stimulations also gave rise to a marked increase of the number of cells double-labeled with the mitotic marker bromodeoxyuridine and NeuN in the subgranular zone and on the hilar border of the dentate granule cell layer. The present data show that single and intermittent, brief seizures induce both apoptotic death and proliferation of dentate gyrus neurons. We hypothesize that these processes, occurring early during epileptogenesis, are primary events in the development of hippocampal pathology in animals and possibly also in patients suffering from temporal lobe epilepsy.
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| 17. |
- Bengzon, Johan, et al.
(författare)
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Neuronal apoptosis after brief and prolonged seizures.
- 2002
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Ingår i: Progress in Brain Research. - 1875-7855. ; 135, s. 111-119
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Forskningsöversikt (refereegranskat)abstract
- Evidence has accumulated that apoptotic cell death contributes to brain damage following experimental seizures. A substantial number of degenerating neurons within limbic regions display morphological features of apoptosis following prolonged seizures evoked by systemic or local injections of kainic acid, systemic injections of pilocarpine and sustained stimulation of the perforant path. Although longer periods of seizures consistently result in brain damage, it has previously not been clear whether brief single or intermittent seizures lead to cell death. However, recent results indicate that also single seizures lead to apoptotic neuronal death. A brief, non-convulsive seizure evoked by kindling stimulation was found to produce apoptotic neurons bilaterally in the rat dentate gyrus. The mechanism triggering and mediating apoptotic degeneration is at present being studied. Alterations in the expression and activity of cell-death regulatory proteins such as members of the Bcl-2 family and the cysteinyl aspartate-specific proteinase (caspase) family occur in regions vulnerable to cell degeneration, suggesting an involvement of these factors in mediating apoptosis following seizures. Findings of decreased apoptotic cell death following administration of caspase inhibitors prior to and following experimentally induced status epilepticus, further suggest a role for caspases in seizure-evoked neuronal degeneration. Intermediate forms of cell death with both necrotic and apoptotic features have been found after seizures and investigation into the detailed mechanisms of the different forms of cell degeneration is needed before attempts to specific prevention can be made.
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| 18. |
- Bengzon, Johan, et al.
(författare)
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Regulation of norepinephrine transporter and tyrosine hydroxylase mRNAs after kainic acid-induced seizures
- 1999
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Ingår i: Brain Research. - 0006-8993. ; 842:1, s. 239-242
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Tidskriftsartikel (refereegranskat)abstract
- Noradrenergic locus coeruleus (LC) efferents to the forebrain suppress seizures in several models of epilepsy. Using in situ hybridization, we demonstrate that tyrosine hydroxylase (TH) and norepinephrine transporter (NET) but not vesicular monoamine transporter 2 (VMAT2) mRNA levels are transiently elevated in LC neurons following kainic acid-induced status epilepticus. These increases of TH and NET mRNAs and presumably of the proteins themselves might enhance synthesis and reuptake of NE postictally.
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| 19. |
- Bengzon, Johan, et al.
(författare)
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Suppression of epileptogenesis by modification of N-methyl-D-aspartate receptor subunit composition
- 1999
-
Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X. ; 11:3, s. 916-922
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Tidskriftsartikel (refereegranskat)abstract
- The effects of altered N-methyl-D-aspartate (NMDA) receptor subunit composition on seizure development in kindling epilepsy were assessed in transgenic mice expressing high neuronal levels of NR2D under control of the calcium/calmodulin kinase II alpha subunit (αCaMKII) promoter. The NR2D subunit is normally present at very low levels in the mature forebrain. Transgenic mice showed a marked reduction of amygdala kindling development. Spread of epileptic activity was retarded acid generalized seizures appeared later in animals overexpressing NR2D compared with wild-type mice. The progressive lengthening of epileptiform activity, which normally occurs in kindling, was also dampened in transgenic animals. We conclude that NMDA receptor subunit composition determines the progression of experimental epilepsy.
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| 20. |
- Bianco, Paolo, et al.
(författare)
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Regulation of stem cell therapies under attack in Europe: for whom the bell tolls
- 2013
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Ingår i: EMBO Journal. - : Wiley. - 1460-2075 .- 0261-4189. ; 32:11, s. 1489-1495
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- At the time of writing, the Italian Parliament is debating a new law that would make it legal to practice an unproven stem cell treatment in public hospitals. The treatment, offered by a private non-medical organization, may not be safe, lacks a rationale, and violates current national laws and European regulations. This case raises multiple concerns, most prominently the urgent need to protect patients who are severely ill, exposed to significant risks, and vulnerable to exploitation. The scientific community must consider the context-social, financial, medical, legal-in which stem cell science is currently situated and the need for stringent regulation. Additional concerns are emerging. These emanate from the novel climate, created within science itself, and stem cell science in particular, by the currently prevailing model of 'translational medicine'. Only rigorous science and rigorous regulation can ensure translation of science into effective therapies rather than into ineffective market products, and mark, at the same time, the sharp distinction between the striving for new therapies and the deceit of patients.
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| 21. |
- Biscaro, Barbara, et al.
(författare)
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A beta Immunotherapy Protects Morphology and Survival of Adult-Born Neurons in Doubly Transgenic APP/PS1 Mice
- 2009
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Ingår i: The Journal of Neuroscience. - 1529-2401. ; 29:45, s. 14108-14119
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampus is heavily affected by progressive neurodegeneration and beta-amyloid pathology in Alzheimer's disease (AD). The hippocampus is also one of the few brain regions that generate new neurons throughout adulthood. Because hippocampal neurogenesis is regulated by both endogenous and environmental factors, we determined whether it benefits from therapeutic reduction of beta-amyloid peptide (A beta)-related toxicity induced by passive A beta immunotherapy. A beta immunotherapy of 8-9-month-old mice expressing familial AD-causing mutations in the amyloid precursor protein and presenilin-1 genes with an antibody against A beta decreased compact beta-amyloid plaque burden and promoted survival of newly born neurons in the hippocampal dentate gyrus. As these neurons matured, they exhibited longer dendrites with more complex arborization compared with newly born neurons in control-treated transgenic littermates. The newly born neurons showed signs of functional integration indicated by expression of the immediate-early gene Zif268 in response to exposure to a novel object. A beta immunotherapy was associated with higher numbers of synaptophysin-positive synaptic boutons. Labeling dividing progenitor cells with a retroviral vector encoding green fluorescent protein (GFP) showed that A beta immunotherapy restored the impaired dendritic branching, as well as the density of dendritic spines in new mature neurons. The presence of cellular prion protein (PrPc) on the dendrites of the GFP(+) newly born neurons is compatible with a putative role of PrPc in mediating A beta-related toxicity in these cells. In addition, passive A beta immunotherapy was accompanied by increased angiogenesis. Our data establish that passive A beta immunotherapy can restore the morphological maturation of the newly formed neurons in the adult hippocampus and promote angiogenesis. These findings provide evidence for a role of A beta immunotherapy in stimulating neurogenesis and angiogenesis in transgenic mouse models of AD, and they suggest the possibility that A beta immunotherapy can recover neuronal and vascular functions in brains with beta-amyloidosis.
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| 22. |
- Biscaro, Barbara, et al.
(författare)
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Inhibition of Microglial Activation Protects Hippocampal Neurogenesis and Improves Cognitive Deficits in a Transgenic Mouse Model for Alzheimer's Disease
- 2012
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Ingår i: Neurodegenerative Diseases. - : S. Karger AG. - 1660-2862 .- 1660-2854. ; 9:4, s. 187-198
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Tidskriftsartikel (refereegranskat)abstract
- Background: Activated microglia with macrophage-like functions invade and surround beta-amyloid (A beta) plaques in Alzheimer's disease (AD), possibly contributing to the turnover of A beta, but they can also secrete proinflammatory factors that may be involved in the pathogenesis of AD. Microglia are known to modulate adult hippocampal neurogenesis. Objectives/Methods: To determine the role of microglia on neurogenesis in brains with A beta pathology, we inhibited microglial activation with the tetracycline derivative minocycline in doubly transgenic mice expressing mutant human amyloid precursor protein (APP) and mutant human presenilin-1 (PS1). Results: Minocycline increased the survival of new dentate granule cells in APP/PS1 mice indicated by more BrdU+/NeuN+ cells as compared to vehicle-treated transgenic littermates, accompanied by improved behavioral performance in a hippocampus-dependent learning task. Both brain levels of A beta and A beta-related morphological deficits in the new neurons labeled with GFP-expressing retrovirus were unaffected in minocycline-treated mice. Conclusions: These results suggest a role for microglia in A beta-related functional deficits and in suppressing the survival of new neurons, and show that modulation of microglial function with minocycline can protect hippocampal neurogenesis in the presence of A beta pathology. Copyright (C) 2012 S. Karger AG, Basel
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| 23. |
- Björklund, Anders, et al.
(författare)
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Replacing Dopamine Neurons in Parkinson's Disease : How did it happen?
- 2017
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Ingår i: Journal of Parkinson's Disease. - 1877-7171. ; 7:s1, s. 23-33
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Forskningsöversikt (refereegranskat)abstract
- The efforts to develop a dopamine cell replacement therapy for Parkinson's disease have spanned over more than three decades. Based on almost 10 years of transplantation studies in animal models, the first patients receiving grafts of fetal-derived dopamine neuroblasts were operated in Lund in 1987. Over the following two decades, a total of 18 patients were transplanted and followed closely by our team with mixed but also very encouraging results. In this article we tell the story of how the preclinical and clinical transplantation program in Lund evolved. We recall the excitement when we obtained the first evidence for survival and function of transplanted neurons in the diseased human brain. We also remember the setbacks that we have experienced during these 30 years and discuss the very interesting developments that are now taking place in this exciting field.
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| 24. |
- Blomqvist, Photjanee, et al.
(författare)
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Cyclic AMP Concentrations in Rat Neocortex and Hippocampus During and Following Incomplete Ischemia : Effects of Central Noradrenergic Neurons, Prostaglandins, and Adenosine
- 1985
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 44:5, s. 1345-1353
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: The concentrations of cyclic AMP, noradrenaline, glycogen, glucose, lactate, pyruvate, labile phosphate compounds, and free fatty acids were investigated in the rat neocortex and hippocampus during and following cerebral ischemia. An incomplete ischemia of 5 and 15 min duration was induced by bilateral carotid clamping combined with hypotension. The postischemic events were studied after 5, 15, and 60 min of recirculation. Five minutes of ischemia did not significantly alter the neocortical or hippocampal concentrations of cyclic AMP. After 15 min of ischemia the neocortical levels decreased significantly below control values. In the recirculation period following ischemia a significant elevation of the cyclic AMP concentrations was observed. Following 5 min of recirculation after 5 min of ischemia the levels increased from 2.53 ± 0.21 nmol ± g−1 to 5.18 ± 0.09 nmol ± g−1 in the neocortex and from 2.14 ± 0.16 nmol ± g−1 to 3.52 ± 0.35 nmol ± g−1 in the hippocampus. Five minutes of recirculation following 15 min of ischemia led to a significant increase in the levels of cyclic AMP, to 12.86 ± 1.43 nmol ± g−1 in the neocortex to 5.58 ± 0.57 nmol ± g−1 in the hippocampus. With longer recirculation periods the cyclic AMP levels progressively decreased and were similar to control values after 60 min. Depletion of cortical noradrenaline by at least 95% was performed by injections of 6‐hydroxydopamine into the ascending axon bundles from the locus ceruleus. The lesion did not significantly change the ischemic or postischemic neocortical and hippocampal levels of cyclic AMP, glycogen, or free fatty acids including arachidonic acid. Treatment of the animals with theophyllamine (23, 46, and 92 mg ± kg−1) or indomethacin (10 mg ± kg−1) did not affect the postischemic levels of cyclic AMP. It is concluded that central noradrenergic neurons, prostaglandins, and adenosine are not of major importance for the observed postischemic elevations of cyclic AMP and that the changes in the concentrations of free fatty acids measured during and following ischemia are not mediated by noradrenergic neurons.
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| 25. |
- Blomqvist, Photjanee, et al.
(författare)
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Lesions of the locus coeruleus system aggravate ischemic damage in the rat brain
- 1985
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940. ; 58:3, s. 353-358
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Tidskriftsartikel (refereegranskat)abstract
- The possibility that the noradrenergic locus coeruleus system influences brain damage following ischemia was explored in rats. Bilateral lesions of the locus coeruleus projections to the forebrain aggravated the neuronal necrosis in the hippocampal CAI region and neocortex following complete cerebral ischemia induced by transient cardiac arrest. These findings provide evidence that the postischemic activation of the inhibitory locus coeruleus system could counteract a possible detrimental neuronal hyperexcitation, thereby limiting neuronal necrosis.
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