title: Evaluating the relationship between amyloid-β and α-synuclein phosphorylated at Ser129 in dementia with Lewy bodies and Parkinson's disease.
abstract: BACKGROUND
  Lewy body and Alzheimer-type pathologies often co-exist. Several studies suggest a synergistic relationship between amyloid-β (Aβ) and α-synuclein (α-syn) accumulation. We have explored the relationship between Aβ accumulation and the phosphorylation of α-syn at serine-129 (pSer129 α-syn), in post-mortem human brain tissue and in SH-SY5Y neuroblastoma cells transfected to overexpress human α-syn.
  
  
  METHODS
  We measured levels of Aβ40, Aβ42, α-syn and pSer129 α-syn by sandwich enzyme-linked immunosorbent assay, in soluble and insoluble fractions of midfrontal, cingulate and parahippocampal cortex and thalamus, from cases of Parkinson's disease (PD) with (PDD; n = 12) and without dementia (PDND; n = 23), dementia with Lewy bodies (DLB; n = 10) and age-matched controls (n = 17). We also examined the relationship of these measurements to cognitive decline, as measured by time-to-dementia and the mini-mental state examination (MMSE) score in the PD patients, and to Braak tangle stage.
  
  
  RESULTS
  In most brain regions, the concentration of insoluble pSer129 α-syn correlated positively, and soluble pSer129 α-syn negatively, with the levels of soluble and insoluble Aβ. Insoluble pSer129 α-syn also correlated positively with Braak stage. In most regions, the levels of insoluble and soluble Aβ and the proportion of insoluble α-syn that was phosphorylated at Ser129 were significantly higher in the PD and DLB groups than the controls, and higher in the PDD and DLB groups than the PDND brains. In PD, the MMSE score correlated negatively with the level of insoluble pSer129 α-syn. Exposure of SH-SY5Y cells to aggregated Aβ42 significantly increased the proportion of α-syn that was phosphorylated at Ser129 (aggregated Aβ40 exposure had a smaller, non-significant effect).
  
  
  CONCLUSIONS
  Together, these data show that the concentration of pSer129 α-syn in brain tissue homogenates is directly related to the level of Aβ and Braak tangle stage, and predicts cognitive status in Lewy body diseases.
authors.affiliation: Dementia Research Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Swirski
authors.affiliation: Dementia Research Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Miners
authors.affiliation: Department of Molecular Neuroscience, Reta Lila Weston Institute of Neurological Studies and Queen Square Brain Bank for Neurological Disorders, Institute of Neurology, University College London, London, UK.
authors.forename: Rohan
authors.initials: R
authors.lastname: de Silva
authors.affiliation: Department of Molecular Neuroscience, Reta Lila Weston Institute of Neurological Studies and Queen Square Brain Bank for Neurological Disorders, Institute of Neurology, University College London, London, UK.
authors.forename: Tammaryn
authors.initials: T
authors.lastname: Lashley
authors.affiliation: Department of Molecular Neuroscience, Reta Lila Weston Institute of Neurological Studies and Queen Square Brain Bank for Neurological Disorders, Institute of Neurology, University College London, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Ling
authors.affiliation: Department of Molecular Neuroscience, Reta Lila Weston Institute of Neurological Studies and Queen Square Brain Bank for Neurological Disorders, Institute of Neurology, University College London, London, UK.
authors.forename: Janice
authors.initials: J
authors.lastname: Holton
authors.affiliation: Department of Molecular Neuroscience, Reta Lila Weston Institute of Neurological Studies and Queen Square Brain Bank for Neurological Disorders, Institute of Neurology, University College London, London, UK.
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.affiliation: Dementia Research Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Seth
authors.initials: S
authors.lastname: Love