Fructuoso Marta, Vermeiren Yannick, Boluda Susana, Stimmer Lev, Crans René A J, Xicota Laura, Eisel Uli, Casan Natalia Orti, Bun Philippe, Duyckaerts Charles, Delabar Jean-Maurice, Strydom Andre, Van Dam Debby, Dierssen Mara, De Deyn Peter, Potier Marie-Claude
Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, APHP, Hôpital de La Pitié-Salpêtrière, INSERM, Paris, France.
Laboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Alzheimers Dement. 2025 Jun;21(6):e70262. doi: 10.1002/alz.70262.
The locus coeruleus (LC), the brain's primary source of noradrenaline (NA), undergoes early neurodegeneration in Parkinson's disease (PD), Alzheimer's diseases (AD), and Down syndrome (DS); however, differences have not been examined in parallel.
Post mortem brains (n = 67) from individuals with AD, DS-AD, and PD without and with dementia (PD-D) and controls were analyzed for amyloid beta (Aβ), phosphorylated tau (pTau), α-synuclein, endo-lysosomal alterations, biogenic amines, and selective biomarkers.
LC degeneration correlated with age, peaking in AD and PD-D, while NA and dopaminergic metabolites were significantly reduced only in PD-D. DS-AD, the youngest group, showed the highest Aβ and pTau levels but the least noradrenergic neuron loss. We demonstrated for the first time that endosomal alterations were present in AD, lysosomal changes were present in PD-D/DS-AD, and DYRK1A, a key protein from chromosome 21, was elevated only in DS-AD.
Loss of noradrenergic neurons may occur independently of amyloid and tau pathologies.
We provide the first analysis of neuropathological and biochemical features including biogenic amines of the LC in AD, DS, and PD. Loss of noradrenergic neurons was most severe in AD and PD. Only in DS, levels of DYRK1A - a kinase encoded on chromosome 21 and implicated in neurodegenerative processes - were elevated and negatively correlated to biogenic amine levels. Although individuals with DS having AD were the youngest group, they had the highest levels of amyloid and tau pathologies, but less noradrenergic neurons loss compared to other disease groups.
蓝斑核（LC）是大脑去甲肾上腺素（NA）的主要来源，在帕金森病（PD）、阿尔茨海默病（AD）和唐氏综合征（DS）中会发生早期神经退行性变；然而，尚未对这些差异进行平行研究。
对来自AD、DS-AD、有无痴呆的PD（PD-D）患者及对照组的67例死后大脑进行分析，检测淀粉样β蛋白（Aβ）、磷酸化tau蛋白（pTau）、α-突触核蛋白、内溶酶体改变、生物胺及选择性生物标志物。
LC变性与年龄相关，在AD和PD-D中达到峰值，而NA和多巴胺能代谢产物仅在PD-D中显著降低。DS-AD是最年轻的组，其Aβ和pTau水平最高，但去甲肾上腺素能神经元损失最少。我们首次证明，内体改变存在于AD中，溶酶体变化存在于PD-D/DS-AD中，而21号染色体上的关键蛋白DYRK1A仅在DS-AD中升高。
去甲肾上腺素能神经元的丧失可能独立于淀粉样蛋白和tau病理改变而发生。
我们首次对AD、DS和PD中包括LC生物胺在内的神经病理和生化特征进行了分析。去甲肾上腺素能神经元的丧失在AD和PD中最为严重。仅在DS中，DYRK1A（一种在21号染色体上编码且与神经退行性过程有关的激酶）水平升高，且与生物胺水平呈负相关。尽管患有AD的DS个体是最年轻的组，但他们的淀粉样蛋白和tau病理水平最高，但与其他疾病组相比，去甲肾上腺素能神经元损失较少。
