| 131. |
- Li, Jia-Yi, et al.
(författare)
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Critical issues of clinical human embryonic stem cell therapy for brain repair.
- 2008
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Ingår i: Trends in Neurosciences. - : Elsevier BV. - 1878-108X .- 0166-2236. ; 31, s. 146-153
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Tidskriftsartikel (refereegranskat)abstract
- Embryonic stem cells (ESCs) provide hope as a potential regenerative therapy for neurological conditions such as Parkinson's disease and spinal cord injury. Currently, ESC-based nervous system repair faces several problems. One major hurdle is related to problems in generating large and defined populations of the desired types of neurons from human ESCs (hESCs). Moreover, survival of grafted hESC-derived cells has varied and functional recovery in recipient animals has often been disappointing. Importantly, in clinical trials, adverse effects after surgery, including tumors or vigorous immune reactions, must be avoided. Here we highlight attempts to overcome these hurdles with hESCs intended for central nervous system repair. We focus on hESC-derived dopamine-producing neurons that can be grafted in Parkinson's disease and identify critical experiments that need to be conducted before clinical trials can occur.
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| 132. |
- Li, Jia-Yi, et al.
(författare)
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GAP 43-like immunoreactivity in normal adult rat sciatic nerve, spinal cord, and motoneurons: axonal transport and effect of spinal cord transection
- 1993
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Ingår i: Neuroscience. - 0306-4522. ; 57:3, s. 759-76
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Tidskriftsartikel (refereegranskat)abstract
- Using immunofluorescence and cytofluorimetric scanning techniques in the rat, the fast anterograde and retrograde axonal transport of growth-associated protein-43-like immunoreactivity in normal sciatic nerves, and after spinal cord transection in the lower thoracic region, were investigated. Spinal roots and motor endplates in the peroneal muscles were also studied. For comparison, anti-synaptophysin (p38) was used. In intact adult animals, the amounts of immunoreactive growth-associated protein-43 increased linearly, both proximally and distally to the crush site, between 1 and 24 h after crushing the sciatic nerve. The accumulations were present in thick as well as in thin axons. Distal accumulations in the sciatic nerve were about 40-60% of the proximal amounts, indicating a recycling of organelles with growth-associated protein-43-like immunoreactivity. During the week after spinal cord transection, no clear changes were observed; the anterograde transport of growth-associated protein-43-like immunoreactivity showed a tendency to decrease at day 1 and then a tendency to increase, reaching 120% of control at seven days (not significant). Transported p38-like immunoreactivity showed similar but smaller changes. In the lumbar spinal cord gray matter many nerve terminals with growth-associated protein-43-like immunoreactivity were seen in intact animals. After spinal transection, these terminals gradually decreased, suggesting that they belonged to descending pathways. However, p38-positive terminals were not obviously decreased. After crushing ventral and dorsal roots, accumulations of pf growth-associated protein-43-like immunoreactivity were present in thick axons in the ventral roots and in thin to medium-sized axons in the dorsal roots. In peroneal muscles, growth-associated protein-43-like immunoreactivity was present in some (but not all) motor endplates in all groups. These results indicate that: (i) growth-associated protein-43 is normally present in nerve terminals of many descending projections of the spinal cord; (ii) growth-associated protein-43-like immunoreactivity is expressed and bidirectionally transported in neurons (motor as well as sensory) of normal sciatic nerves; (iii) growth-associated protein-43-like immunoreactivity is present in some adult motor endplates; and (iv) inhibited supraspinal input causes minor, if any, alterations--paralleled by p38--in axonal transport of growth-associated protein-43-like immunoreactivity.
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| 133. |
- Li, Jia-Yi, et al.
(författare)
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Grafting dopamine neurons in Parkinson's disease: do stem cells have a role in the future?
- 2003
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 85:Suppl 2, s. 13-13
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) patients display motor symptoms, e.g. tremor, rigidity and bradykinesia, largely due to a dramatic loss of dopaminergic neurons in the substantia nigra. Grafts of human embryonic dopamine neurons can survive in the striatum and reduce several of the motor symptoms. Several lines of evidence suggest that a crucial threshold of surviving dopaminergic neurons must be exceeded for the grafts to become functional and relieve symptoms. A relatively small number of operations have been performed so far. The major obstacle to large clinical trials has been that tissue from large numbers of donor embryos is needed for each patient. Thus, there is definitely a need for alternative sources of donor tissue for grafting in PD. Clearly various forms of stem cells are interesting options. This presentation will focus the possible future use of embryonic stem cells and bone marrow stem cells as donor tissue for transplantation in PD.
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| 134. |
- Li, Jia-Yi, et al.
(författare)
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Huntington's disease: a synaptopathy?
- 2003
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Ingår i: Trends in Molecular Medicine. - : Elsevier BV. - 1471-4914. ; 9:10, s. 414-420
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is caused by a polyglutamine expansion in the protein huntingtin. In its terminal stage, HD is characterized by widespread neuronal death in the neocortex and the striatum. Classically, this neuronal death has been thought to underlie most of the symptoms of the disease. Accumulating evidence suggests, however, that cellular dysfunction is important in the pathogenesis of HD. We propose that specific impairment of the exocytosis and endocytosis machinery contributes to the development of HD. We also suggest that abnormal synaptic transmission underlies the early symptoms of HD and can contribute to the triggering of cell death in later stages of the disease.
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| 135. |
- Li, Jia-Yi, et al.
(författare)
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Influence of spinal cord transection on the presence and axonal transport of CGRP-, chromogranin A-, VIP-, synapsin I-, and synaptophysin-like immunoreactivities in rat motor nerve
- 1992
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Ingår i: J Neurobiol. - 0022-3034. ; 23:8, s. 1094-110
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Tidskriftsartikel (refereegranskat)abstract
- Using immunofluorescence and cytofluorimetric scanning (CFS), we investigated the short-term (1-7 days) influence of lower thoracic spinal cord transection on lumbar motor neurons. The content of calcitonin gene-related peptide- (CGRP) like immunoreactivity (LI), chromogranin A (Chr A)-LI, vasoactive intestinal polypeptide (VIP)-LI, Syn I-LI, and synaptophysin (p38)-LI in motor perikarya, and the anterograde and retrograde axonal transport of these substances in the sciatic nerve, were studied in nerve crush (6 h) experiments. During the week after transection, CGRP-LI in perikarya decreased, whereas Chr A-LI increased. VIP-LI, co-localized with Chr A-LI in motor perikarya, did not change after transection. The antero- and retrograde transport of CGRP-LI in the sciatic nerve, occurring in both motor and sensory axons, appeared unchanged in cytofluorimetric scanning (CFS) graphs, but the microscopical picture clearly showed that large motor axons had a decreased content of CGRP-LI at 3 and 7 days posttransection, whereas thinner axons were unchanged in fluorescence intensity. The anterograde transport of Chr A-LI, present in both motor and postganglionic adrenergic axons, was decreased 1 and 3 days after lesion, but returned to control by day 7. There was a marked decrease in anterograde transport of VIP-LI, present mainly in postganglionic sympathetic axons, at day 3, but at 7 days transport was normal. The amounts of transported p38, the synaptic vesicle marker, were in the normal range during the whole period. Syn I-LI accumulation anterogradely was somewhat decreased at 3 and 7 days posttransection, and at 1 day the retrograde accumulation was significantly increased. The results suggest that removal of supraspinal input to intact lower motor neurons causes alterations in metabolism and axonal transport of organelle-associated substances, partly probably related to the complex pattern of transmitter leakage from degenerating, descending nerve terminals. These alterations appear to take place also in postganglionic sympathetic neurons in the sciatic nerve, that originate in the lumbar sympathetic chain.
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| 136. |
- Li, Jia-Yi, et al.
(författare)
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Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation.
- 2008
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 14, s. 501-503
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Tidskriftsartikel (refereegranskat)abstract
- Two subjects with Parkinson's disease who had long-term survival of transplanted fetal mesencephalic dopaminergic neurons (11-16 years) developed alpha-synuclein-positive Lewy bodies in grafted neurons. Our observation has key implications for understanding Parkinson's pathogenesis by providing the first evidence, to our knowledge, that the disease can propagate from host to graft cells. However, available data suggest that the majority of grafted cells are functionally unimpaired after a decade, and recipients can still experience long-term symptomatic relief.
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| 137. |
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| 138. |
- Li, Jia-Yi, et al.
(författare)
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The use of the R6 transgenic mouse models of Huntington's disease in attempts to develop novel therapeutic strategies.
- 2005
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Ingår i: NeuroRx. - : Springer Science and Business Media LLC. - 1545-5343. ; 2:3, s. 64-447
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is a genetic neurodegenerative disorder. Since identification of the disease-causing gene in 1993, a number of genetically modified animal models of HD have been generated. The first transgenic mouse models, R6/1 and R6/2 lines, were established 8 years ago. The R6/2 mice have been the best characterized and the most widely used model to study pathogenesis of HD and therapeutic interventions. In the present review, we especially focus on the characteristics of R6 transgenic mouse models and, in greater detail, describe the different therapeutic strategies that have been tested in these mice. We also, at the end, critically assess the relevance of the HD mouse models compared with the human disease and discuss how they can be best used in the future.
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| 139. |
- Liu, Zongran, et al.
(författare)
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The cervical lymph node contributes to peripheral inflammation related to Parkinson’s disease
- 2023
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Ingår i: Journal of Neuroinflammation. - 1742-2094. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Peripheral inflammation is an important feature of Parkinson’s disease (PD). However, if and how CNS pathology is involved in the peripheral inflammation in PD remains to be fully investigated. Recently, the existence of meningeal lymphatics and its involvement in draining cerebral spinal fluid (CSF) to the cervical lymph node has been discovered. It is known that meningeal lymphatic dysfunction exists in idiopathic PD. The deep cervical lymph node (dCLN) substantially contributes to the drainage of the meningeal lymphatics. In addition, one of the lymphatics draining components, CSF, contains abundant α-synuclein (α-syn), a protein critically involved in PD pathogenesis and neuroinflammation. Thus, we began with exploring the possible structural and functional alterations of the dCLN in a PD mouse model (A53T mice) and investigated the role of pathological α-syn in peripheral inflammation and its potential underlying molecular mechanisms. Methods: In this study, the transgenic mice (prnp-SNCA*A53T) which specifically overexpressed A53T mutant α-syn in CNS were employed as the PD animal model. Immunofluorescent and Hematoxylin and eosin staining were used to evaluate structure of dCLN. Inflammation in dCLNs as well as in bone-marrow-derived macrophages (BMDMs) was assessed quantitatively by measuring the mRNA and protein levels of typical inflammatory cytokines (including IL-1β, IL-6 and TNF-α). Intra-cisterna magna injection, flow cytometric sorting and electrochemiluminescence immunoassays were applied to investigate the lymphatic drainage of α-syn from the CNS. RNA-seq and Western blot were used to explore how pathological α-syn mediated the inflammation in PD mice. Results: The results unequivocally revealed substantially enlarged dCLNs, along with slow lymphatic flow, and increased inflammation in the dCLNs of A53T mice. Oligomeric α-syn drained from CSF potently activated macrophages in the dCLN via endoplasmic reticulum (ER) stress. Notably, inhibition of ER stress effectively suppressed peripheral inflammation in PD mice. Conclusions: Our findings indicate that lymph node enlargement is closely related to macrophage activation, induced by meningeal lymphatics draining oligomeric α-syn, and contributes to the peripheral inflammation in PD. In addition, ER stress is a potential therapeutic target to ameliorate PD pathogenesis.
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| 140. |
- Martinsson, Isak, et al.
(författare)
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Aβ/Amyloid Precursor Protein-Induced Hyperexcitability and Dysregulation of Homeostatic Synaptic Plasticity in Neuron Models of Alzheimer’s Disease
- 2022
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is increasingly seen as a disease of synapses and diverse evidence has implicated the amyloid-β peptide (Aβ) in synapse damage. The molecular and cellular mechanism(s) by which Aβ and/or its precursor protein, the amyloid precursor protein (APP) can affect synapses remains unclear. Interestingly, early hyperexcitability has been described in human AD and mouse models of AD, which precedes later hypoactivity. Here we show that neurons in culture with either elevated levels of Aβ or with human APP mutated to prevent Aβ generation can both induce hyperactivity as detected by elevated calcium transient frequency and amplitude. Since homeostatic synaptic plasticity (HSP) mechanisms normally maintain a setpoint of activity, we examined whether HSP was altered in AD transgenic neurons. Using methods known to induce HSP, we demonstrate that APP protein levels are regulated by chronic modulation of activity and that AD transgenic neurons have an impaired adaptation of calcium transients to global changes in activity. Further, AD transgenic compared to WT neurons failed to adjust the length of their axon initial segments (AIS), an adaptation known to alter excitability. Thus, we show that both APP and Aβ influence neuronal activity and that mechanisms of HSP are disrupted in primary neuron models of AD.
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