Aumont Etienne, Tremblay Cyntia, Levert Stéphanie, Bennett David A, Calon Frédéric, Leclerc Nicole
Département de psychologie de l'Université du Québec à Montréal, Montréal, QC, Canada.
Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, QC, Canada.
Front Aging Neurosci. 2022 Nov 24;14:1038343. doi: 10.3389/fnagi.2022.1038343. eCollection 2022.
Alzheimer's disease (AD) is a multifactorial disorder diagnosed through the assessment of amyloid-beta (Aβ) and tau protein depositions. Filamin A (FLNA) could be a key partner of both Aβ and tau pathological processes and may be an important contributor to AD progression. The main aim of this study was to describe the differences in FLNA levels across clinicopathologic groups.
From parietal cortex samples of 57 individuals (19 with no cognitive impairment (NCI), 19 mild cognitively impaired (MCI) and 19 with dementia) from the Religious Orders Study (ROS), we quantified total tau, phosphorylated tau (pTau), FLNA, synaptophysin, vesicular acetylcholine transporters (VAChT) and choline acetyltransferase (ChAT) by Western blot. Aβ42 and neuritic plaques (NP) were quantified by ELISA and Bielschowsky silver impregnation, respectively. AD staging was determined using ABC method combining Thal, Braak and the CERAD staging. From this, clinicopathologic stages of AD were established by subdividing subjects with neuropathological AD between preclinical AD, prodromal AD and AD dementia (ADD). Receiver operating characteristics analyses were performed to predict AD neuropathology from FLNA quantifications.
Insoluble FLNA was significantly and positively correlated with Aβ42, NP, Thal stages, ABC scores and AD clinicopathologic stages ( < 0.05 False discovery rate-corrected). No correlation of FLNA with tau measures was found. Insoluble FLNA levels were significantly higher in the prodromal AD, ADD and intermediate ABC groups. This was consistent with significantly lower levels of soluble FLNA specifically in prodromal AD. Insoluble (AUC: 0.830) and soluble FLNA levels (AUC: 0.830) as well as the ratio of soluble over insoluble FLNA (AUC: 0.852), were excellent predictors of prodromal AD among subjects with MCI from the ROS cohort.
We observed opposite level changes between insoluble and soluble FLNA in prodromal AD. As this stage coincides with the appearance of cognitive symptoms, this may be a key event in the transition from preclinical to prodromal AD. Insoluble FLNA could be useful to identify prodromal AD among subjects with an MCI, indicating that it might be a hallmark of prodromal AD.
阿尔茨海默病（AD）是一种多因素疾病，通过评估淀粉样β蛋白（Aβ）和tau蛋白沉积来诊断。细丝蛋白A（FLNA）可能是Aβ和tau病理过程的关键伙伴，可能是AD进展的重要促成因素。本研究的主要目的是描述不同临床病理组中FLNA水平的差异。
从宗教团体研究（ROS）中57名个体（19名无认知障碍（NCI）、19名轻度认知障碍（MCI）和19名患有痴呆症）的顶叶皮质样本中，我们通过蛋白质印迹法对总tau、磷酸化tau（pTau）、FLNA、突触素、囊泡乙酰胆碱转运体（VAChT）和胆碱乙酰转移酶（ChAT）进行定量。分别通过酶联免疫吸附测定法（ELISA）和 Bielschowsky 银浸染法对Aβ42和神经炎性斑块（NP）进行定量。使用结合了Thal、Braak和CERAD分期的ABC方法确定AD分期。据此，通过将神经病理学AD患者细分为临床前期AD、前驱期AD和AD痴呆（ADD）来确定AD的临床病理阶段。进行受试者操作特征分析以从FLNA定量预测AD神经病理学。
不可溶性FLNA与Aβ42、NP、Thal分期、ABC评分和AD临床病理阶段显著正相关（经错误发现率校正，<0.05）。未发现FLNA与tau测量值之间存在相关性。前驱期AD、ADD和ABC中间组中不可溶性FLNA水平显著更高。这与特别是前驱期AD中可溶性FLNA水平显著降低一致。在ROS队列的MCI受试者中，不可溶性（曲线下面积：0.830）和可溶性FLNA水平（曲线下面积：0.830）以及可溶性与不可溶性FLNA的比率（曲线下面积：0.852）是前驱期AD的优秀预测指标。
我们观察到前驱期AD中不可溶性和可溶性FLNA之间存在相反的水平变化。由于这个阶段与认知症状的出现相吻合，这可能是从临床前期到前驱期AD转变的关键事件。不可溶性FLNA可能有助于在MCI受试者中识别前驱期AD，表明它可能是前驱期AD的一个标志。
