Dementia Research Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol, UK.
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.
Alzheimers Res Ther. 2014 Dec 1;6(5-8):77. doi: 10.1186/s13195-014-0077-y. eCollection 2014.
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.
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.
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).
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.
路易体和阿尔茨海默病型病理学经常共存。几项研究表明，淀粉样蛋白-β（Aβ）和α-突触核蛋白（α-syn）积累之间存在协同关系。我们已经探索了在死后人脑组织和转染过表达人α-syn 的 SH-SY5Y 神经母细胞瘤细胞中，Aβ 积累与α-syn 丝氨酸-129 位磷酸化（pSer129 α-syn）之间的关系。
我们通过夹心酶联免疫吸附试验测量了中前额叶、扣带回和海马旁皮质以及丘脑可溶性和不溶性部分的 Aβ40、Aβ42、α-syn 和 pSer129 α-syn 的水平，来自帕金森病（PD）伴有痴呆（PDD；n = 12）和不伴有痴呆（PDND；n = 23）、路易体痴呆（DLB；n = 10）和年龄匹配对照（n = 17）的病例。我们还研究了这些测量值与 PD 患者认知能力下降（用痴呆时间和迷你精神状态检查（MMSE）评分衡量）和 Braak 缠结阶段的关系。
在大多数脑区，不溶性 pSer129 α-syn 的浓度与可溶性和不溶性 Aβ 的水平呈正相关，而可溶性 pSer129 α-syn 与可溶性 Aβ 的水平呈负相关。不溶性 pSer129 α-syn 也与 Braak 阶段呈正相关。在大多数区域，PD 和 DLB 组的不溶性和可溶性 Aβ 水平以及在 Ser129 磷酸化的可溶性 α-syn 比例均显著高于对照组，而 PDD 和 DLB 组则高于 PDND 脑。在 PD 中，MMSE 评分与不溶性 pSer129 α-syn 水平呈负相关。SH-SY5Y 细胞暴露于聚集的 Aβ42 显著增加了α-syn 丝氨酸-129 位磷酸化的比例（聚集的 Aβ40 暴露的影响较小，没有统计学意义）。
综上所述，这些数据表明脑组织匀浆中 pSer129 α-syn 的浓度与 Aβ 水平和 Braak 缠结阶段直接相关，并预测路易体疾病的认知状态。
