Synaptic phosphorylated alpha-synuclein in dementia with Lewy bodies
Por:
Colom-Cadena, M, Pegueroles, J, Herrmann, AG, Henstridge, CM, Munoz, L, Querol-Vilaseca, M, Martin-Paniello, C, Luque-Cabecerans, J, Clarimon, J, Belbin, O, Nunez-Llaves, R, Blesa, R, Smith, C, McKenzie, CA, Frosch, MP, Roe, A, Fortea, J, Andilla, J, Loza-Alvarez, P, Gelpi, E, Hyman, BT, Spires-Jones, TL, Lleo, A
Publicada:
1 dic 2017
Resumen:
Synaptic loss occurs early in dementia with Lewy bodies (DLB), but its relationship to alpha-synuclein pathology remains unclear. Using array tomography microscopy, Colom-Cadena et al. reveal small phosphorylated alpha-synuclein aggregates at synaptic terminals of DLB cases, supporting a direct association between alpha-synuclein accumulation and synaptic dysfunction.Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated alpha-synuclein phosphorylated at Ser129. Although phosphorylated alpha-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other alpha-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated alpha-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer's disease and five healthy control subjects to analyse the presence of phosphorylated alpha-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated alpha-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (< 0.16 A mu m(3)). Between 19% and 25% of phosphorylated alpha-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated alpha-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated alpha-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated alpha-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated alpha-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated alpha-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.
Filiaciones:
Colom-Cadena, M:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, Inst Invest Biomed St Pau,Hosp St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Pegueroles, J:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, Inst Invest Biomed St Pau,Hosp St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Herrmann, AG:
Univ Edinburgh, UK Dementia Res Inst, Ctr Discovery Brain Sci, Edinburgh Neurosci,Euan MacDonald Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland
Ctr Dementia Prevent, Edinburgh EH8 9JZ, Midlothian, Scotland
Henstridge, CM:
Univ Edinburgh, UK Dementia Res Inst, Ctr Discovery Brain Sci, Edinburgh Neurosci,Euan MacDonald Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland
Ctr Dementia Prevent, Edinburgh EH8 9JZ, Midlothian, Scotland
Munoz, L:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, Inst Invest Biomed St Pau,Hosp St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Querol-Vilaseca, M:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, Inst Invest Biomed St Pau,Hosp St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Martin-Paniello, C:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, Inst Invest Biomed St Pau,Hosp St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Luque-Cabecerans, J:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, Inst Invest Biomed St Pau,Hosp St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Clarimon, J:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, Inst Invest Biomed St Pau,Hosp St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Belbin, O:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, Inst Invest Biomed St Pau,Hosp St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Nunez-Llaves, R:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, Inst Invest Biomed St Pau,Hosp St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Blesa, R:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, Inst Invest Biomed St Pau,Hosp St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Smith, C:
Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland
McKenzie, CA:
Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland
Frosch, MP:
Massachusetts Gen Hosp, Charlestown, MA USA
Harvard Med Sch, Charlestown, MA USA
Roe, A:
Massachusetts Gen Hosp, Charlestown, MA USA
Harvard Med Sch, Charlestown, MA USA
Fortea, J:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, Inst Invest Biomed St Pau,Hosp St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Andilla, J:
Barcelona Inst Sci & Technol, ICFO Inst Ciencies Foton, Barcelona, Spain
Loza-Alvarez, P:
Barcelona Inst Sci & Technol, ICFO Inst Ciencies Foton, Barcelona, Spain
Gelpi, E:
Biobanc Hosp, Neurol Tissue Bank, Clin IDIBAPS, Barcelona, Spain
Hyman, BT:
Massachusetts Gen Hosp, Charlestown, MA USA
Harvard Med Sch, Charlestown, MA USA
Spires-Jones, TL:
Univ Edinburgh, UK Dementia Res Inst, Ctr Discovery Brain Sci, Edinburgh Neurosci,Euan MacDonald Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland
Ctr Dementia Prevent, Edinburgh EH8 9JZ, Midlothian, Scotland
Lleo, A:
Univ Autonoma Barcelona, Memory Unit, Dept Neurol, Inst Invest Biomed St Pau,Hosp St Pau, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Green Published, Bronze
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