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2.018 Neuropathology of conditional alpha-synuclein transgenic mouse models of Parkinson's disease
S90
Tuesday, 11 December 2007
Results: The most complicated adverse effect of this drug is induction of dyskinesia after chronic treatment for 4−10 years. The two most important factors, which cause L-DOPA induced dyskinesia, are increased activity of the kappa opioid receptor by dynorphin and increased GABA formation by glutamic acid decarboxylase. Both these chemical changes are caused by upregulation of prodynorphin mRNA and glutamic acid dehydrogenase mRNA, respectively, after chronic L-DOPA therapy as a result of gene expression. The ultimate effect is to reinforce the inhibitory output from the internal segment of globus pallidus to thalamus, which results in increased excitatory output from the thalamus to the cerebral cortex causing dyskinesia. Other important reinforcing factors are dopamine release from 5-HT terminals and subcellular increase of synaptic proteins PSD-95 and SAP97 are present in the striatum of L-DOPA-induced dyskinesia. Conclusion: Several hypotheses are available to prevent DID which will be discussed in detail in text. The intrastriatal infusion of fosB antisense and 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4triazolo[1,5-c]pyrimidine (SCH58261) have been reported for the correction of these molecular mechanisms. Prevention of these changes is hoped to prevent L-DOPA induced dyskinesia. 2.016 The severity of L-DOPA-induced dyskinesia in the rat is positively correlated with the density of striatal serotonin afferents D. Rylander1° , E. Strome, F. Mela, G. Mercanti, M.A. Cenci Sweden
1 Lund,
Objective: This study compares the extent of damage to forebrain dopamine (DA), serotonin (5-HT) and noradrenaline (NA) afferent systems caused by 6-hydroxydopamine (6-OHDA) injection in the medial forebrain bundle (MFB) in the rat. The main purpose of the study is to examine possible correlations between damage to the above monoamine systems and the severity of L-DOPA-induced dyskinesia. Method: Thirty-six animals with unilateral 6-OHDA-MFB lesions and substantial motor deficit were selected for a 3-weeks course of L-DOPAtreatment with ratings of abnormal involuntary movements (AIMs). The integrity of DA, 5-HT and NA projections to the striatum, and neocortex was assessed autoradiographically using tritiated ligands for specific neurotransmitter transporters (DAT, SERT and NAT). Results: Rats had a severe (>80%) loss of striatal DAT binding ipsilaterally to the lesion. The extent of striatal DA denervation did not correlate with the L-DOPA-induced AIM scores. In addition to the loss of DAT binding, the 6-OHDA lesion caused an ipsilateral depletion of SERT and NAT binding in the striatum and the sensorimotor cortex (~60% and ~75% for SERT and NAT, respectively). The density of SERT binding in the striatum was positively correlated with the L-DOPA-induced AIM scores (r = 0.537, P = 0.002), being significantly larger in L-DOPA-treated rats that developed AIMs compared to non-dyskinetic cases. No correlation was found between AIMs and striatal or cortical NAT binding densities. Conclusion: In a Parkinson model with nearly complete DA denervation, the severity of L-DOPA induced dyskinesia does not correlate with DAT radioligand-binding, but is positively and linearly related to SERT binding levels in the striatum. This suggests that, for the same extent of nigrostriatal lesion, rats endowed with a higher capacity for L-DOPA conversion in serotonergic neurons have a higher risk to develop AIMs.
Method: Brain tissue from aged, neurologically unimpaired individuals (n = 76), Parkinson (PD: n = 12) and Alzheimer (AD: n = 13) patients were obtained from the Netherlands Brain Bank. Paraffin sections of the olfactory bulb, brainstem and limbic regions were cut and stained for alpha-synuclein and hyperphosphorylated tau using immunohistochemistry. Lewy body pathology and tangle pathology was scored semi-quantitatively on sections collected throughout the regions. Braak staging was evaluated for all cases. Results: Twenty percent (17/76) of the aged individuals had alphasynuclein pathology and 87% (31/34) had tau pathology in the olfactory bulb. All cases with alpha-synuclein pathology in the dorsal motor nucleus of the vagal nerve exhibited alpha-synuclein pathology in the olfactory bulb. Few aged individuals had alpha-synuclein and tau pathology in the olfactory bulb, amygdala and entorhinal cortex without involvement of brainstem regions (8/17). In almost all aged individuals, the substantia nigra pars compacta was intact and did not reveal any Lewy bodies or neurites. All PD cases revealed alpha-synuclein pathology in the olfactory bulb, brainstem and limbic regions (12/12). All AD cases revealed tau pathology in olfactory bulb and limbic regions. Few AD cases revealed alpha-synuclein pathology in brainstem regions (4/13). Conclusion: These data (1) largely confirm Braak’s staging of alphasynuclein pathology in the brainstem and olfactory bulb; (2) suggest that olfactory and limbic alpha-synuclein pathology can co-occur without brainstem pathology; (3) illustrate the high incidence of alpha-synuclein and tau pathology in the olfactory bulb of aged individuals. Non-random samplings might introduce a selection bias. Therefore our numbers may not reflect true population estimates.
2.018 Neuropathology of conditional alpha-synuclein transgenic mouse models of Parkinson’s disease S. Nuber1° , E. Petrasch-Parwez, B. Winner, J. Winkler, S. von H¨orsten, P. Teismann, J.B. Schulz, M. Neumann, M. Fendt, F.N. Gellerich, O. Riess 1 Tuebingen, Germany Alpha-synuclein has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson’s disease (PD). PD is based on progressive neuropathological alterations leading to motor abnormalities that are frequently predated by olfactory dysfunction and often accompanied by cognitive decline in later stages of the disease. Whether the neurodegenerative process might be halted or even reversed is presently unknown. In order to explore whether alpha-synuclein induces these alterations we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wildtype alpha-synuclein in several brain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration, leading to progressive motor decline and impaired long-term memory. Turning off transgene expression in aged mice halted progression of motor symptoms but did not reverse the symptoms. Mice expressing the mutated (A30P) alpha-synuclein limited to the olfactory bulb showed a reduction of monoamines in this region. In a conducted TMT-smell test these mice also revealed an impaired anxiety reaction and an increased exploratory behavior; the latter might be a depressive core symptom. Our data suggest that approaches targeting a-syn induced pathological pathways might be of benefit in early disease stages.
2.017 Pattern of a-synuclein and phosphorylated tau pathology in the olfactory bulb, brainstem and limbic regions in aged individuals
2.019 Identification of modifiers of alpha-synuclein inclusion in a C. elegans model by genome-wide RNAi
W. van de Berg1° , S. Zweekhorst, P. Voorn, H. Groenewegen, P. Hoogland, A.M. Rozemuller 1 Amsterdam, Netherlands
1 Groningen,
Objective: To test the hypothesis that pathology in the olfactory bulb is related to pathology in the brainstem and limbic regions in non-demented individuals above the age of 45 years.
T. van Ham1° , K. Thijssen, R. Breitling, R. Hofstra, R. Plasterk, E. Nollen Netherlands
Objective: The protein alpha-synuclein is tightly connected to development of Parkinson’s disease: hallmark of PD is the presence of protein inclusions in the brain containing the protein alpha-synuclein. In addition, multiplication of the alpha-synuclein gene has been shown to be causative
Tuesday, 11 December 2007
Results: The most complicated adverse effect of this drug is induction of dyskinesia after chronic treatment for 4−10 years. The two most important factors, which cause L-DOPA induced dyskinesia, are increased activity of the kappa opioid receptor by dynorphin and increased GABA formation by glutamic acid decarboxylase. Both these chemical changes are caused by upregulation of prodynorphin mRNA and glutamic acid dehydrogenase mRNA, respectively, after chronic L-DOPA therapy as a result of gene expression. The ultimate effect is to reinforce the inhibitory output from the internal segment of globus pallidus to thalamus, which results in increased excitatory output from the thalamus to the cerebral cortex causing dyskinesia. Other important reinforcing factors are dopamine release from 5-HT terminals and subcellular increase of synaptic proteins PSD-95 and SAP97 are present in the striatum of L-DOPA-induced dyskinesia. Conclusion: Several hypotheses are available to prevent DID which will be discussed in detail in text. The intrastriatal infusion of fosB antisense and 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4triazolo[1,5-c]pyrimidine (SCH58261) have been reported for the correction of these molecular mechanisms. Prevention of these changes is hoped to prevent L-DOPA induced dyskinesia. 2.016 The severity of L-DOPA-induced dyskinesia in the rat is positively correlated with the density of striatal serotonin afferents D. Rylander1° , E. Strome, F. Mela, G. Mercanti, M.A. Cenci Sweden
1 Lund,
Objective: This study compares the extent of damage to forebrain dopamine (DA), serotonin (5-HT) and noradrenaline (NA) afferent systems caused by 6-hydroxydopamine (6-OHDA) injection in the medial forebrain bundle (MFB) in the rat. The main purpose of the study is to examine possible correlations between damage to the above monoamine systems and the severity of L-DOPA-induced dyskinesia. Method: Thirty-six animals with unilateral 6-OHDA-MFB lesions and substantial motor deficit were selected for a 3-weeks course of L-DOPAtreatment with ratings of abnormal involuntary movements (AIMs). The integrity of DA, 5-HT and NA projections to the striatum, and neocortex was assessed autoradiographically using tritiated ligands for specific neurotransmitter transporters (DAT, SERT and NAT). Results: Rats had a severe (>80%) loss of striatal DAT binding ipsilaterally to the lesion. The extent of striatal DA denervation did not correlate with the L-DOPA-induced AIM scores. In addition to the loss of DAT binding, the 6-OHDA lesion caused an ipsilateral depletion of SERT and NAT binding in the striatum and the sensorimotor cortex (~60% and ~75% for SERT and NAT, respectively). The density of SERT binding in the striatum was positively correlated with the L-DOPA-induced AIM scores (r = 0.537, P = 0.002), being significantly larger in L-DOPA-treated rats that developed AIMs compared to non-dyskinetic cases. No correlation was found between AIMs and striatal or cortical NAT binding densities. Conclusion: In a Parkinson model with nearly complete DA denervation, the severity of L-DOPA induced dyskinesia does not correlate with DAT radioligand-binding, but is positively and linearly related to SERT binding levels in the striatum. This suggests that, for the same extent of nigrostriatal lesion, rats endowed with a higher capacity for L-DOPA conversion in serotonergic neurons have a higher risk to develop AIMs.
Method: Brain tissue from aged, neurologically unimpaired individuals (n = 76), Parkinson (PD: n = 12) and Alzheimer (AD: n = 13) patients were obtained from the Netherlands Brain Bank. Paraffin sections of the olfactory bulb, brainstem and limbic regions were cut and stained for alpha-synuclein and hyperphosphorylated tau using immunohistochemistry. Lewy body pathology and tangle pathology was scored semi-quantitatively on sections collected throughout the regions. Braak staging was evaluated for all cases. Results: Twenty percent (17/76) of the aged individuals had alphasynuclein pathology and 87% (31/34) had tau pathology in the olfactory bulb. All cases with alpha-synuclein pathology in the dorsal motor nucleus of the vagal nerve exhibited alpha-synuclein pathology in the olfactory bulb. Few aged individuals had alpha-synuclein and tau pathology in the olfactory bulb, amygdala and entorhinal cortex without involvement of brainstem regions (8/17). In almost all aged individuals, the substantia nigra pars compacta was intact and did not reveal any Lewy bodies or neurites. All PD cases revealed alpha-synuclein pathology in the olfactory bulb, brainstem and limbic regions (12/12). All AD cases revealed tau pathology in olfactory bulb and limbic regions. Few AD cases revealed alpha-synuclein pathology in brainstem regions (4/13). Conclusion: These data (1) largely confirm Braak’s staging of alphasynuclein pathology in the brainstem and olfactory bulb; (2) suggest that olfactory and limbic alpha-synuclein pathology can co-occur without brainstem pathology; (3) illustrate the high incidence of alpha-synuclein and tau pathology in the olfactory bulb of aged individuals. Non-random samplings might introduce a selection bias. Therefore our numbers may not reflect true population estimates.
2.018 Neuropathology of conditional alpha-synuclein transgenic mouse models of Parkinson’s disease S. Nuber1° , E. Petrasch-Parwez, B. Winner, J. Winkler, S. von H¨orsten, P. Teismann, J.B. Schulz, M. Neumann, M. Fendt, F.N. Gellerich, O. Riess 1 Tuebingen, Germany Alpha-synuclein has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson’s disease (PD). PD is based on progressive neuropathological alterations leading to motor abnormalities that are frequently predated by olfactory dysfunction and often accompanied by cognitive decline in later stages of the disease. Whether the neurodegenerative process might be halted or even reversed is presently unknown. In order to explore whether alpha-synuclein induces these alterations we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wildtype alpha-synuclein in several brain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration, leading to progressive motor decline and impaired long-term memory. Turning off transgene expression in aged mice halted progression of motor symptoms but did not reverse the symptoms. Mice expressing the mutated (A30P) alpha-synuclein limited to the olfactory bulb showed a reduction of monoamines in this region. In a conducted TMT-smell test these mice also revealed an impaired anxiety reaction and an increased exploratory behavior; the latter might be a depressive core symptom. Our data suggest that approaches targeting a-syn induced pathological pathways might be of benefit in early disease stages.
2.017 Pattern of a-synuclein and phosphorylated tau pathology in the olfactory bulb, brainstem and limbic regions in aged individuals
2.019 Identification of modifiers of alpha-synuclein inclusion in a C. elegans model by genome-wide RNAi
W. van de Berg1° , S. Zweekhorst, P. Voorn, H. Groenewegen, P. Hoogland, A.M. Rozemuller 1 Amsterdam, Netherlands
1 Groningen,
Objective: To test the hypothesis that pathology in the olfactory bulb is related to pathology in the brainstem and limbic regions in non-demented individuals above the age of 45 years.
T. van Ham1° , K. Thijssen, R. Breitling, R. Hofstra, R. Plasterk, E. Nollen Netherlands
Objective: The protein alpha-synuclein is tightly connected to development of Parkinson’s disease: hallmark of PD is the presence of protein inclusions in the brain containing the protein alpha-synuclein. In addition, multiplication of the alpha-synuclein gene has been shown to be causative