CRIB, Neuroplasticity and Neurodegeneration Laboratory, Ciudad Real Medical School, University of Castilla-La Mancha, 13071 Ciudad Real, Spain.
Int J Mol Sci. 2021 Dec 23;23(1):165. doi: 10.3390/ijms23010165.
Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, is characterized by executive dysfunction and memory impairment mediated by the accumulation of extracellular amyloid-β peptide (Aβ) and intracellular hyperphosphorylated tau protein. The hippocampus (HIPP) is essential for memory formation and is involved in early stages of disease. In fact, hippocampal atrophy is used as an early biomarker of neuronal injury and to evaluate disease progression. It is not yet well-understood whether changes in hippocampal volume are due to neuronal or glial loss. The aim of the study was to assess hippocampal atrophy and/or gliosis using unbiased stereological quantification and to obtain hippocampal proteomic profiles related to neurodegeneration and gliosis. Hippocampal volume measurement, stereological quantification of NeuN-, Iba-1- and GFAP-positive cells, and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS) analysis were performed in AD and non-AD cases. Reduced hippocampal volume was identified using the Cavalieri probe, particularly in the CA1 region, where it correlated with neuronal loss and astrogliosis. A total of 102 downregulated and 47 upregulated proteins were identified in the SWATH-MS analysis after restrictive filtering based on an FC > 1.5 and value < 0.01. The Hsp90 family of chaperones, particularly BAG3 and HSP90AB1, are closely related to astrocytes, indicating a possible role in degrading Aβ and tau through chaperone-mediated autophagy.
阿尔茨海默病（AD）是最常见的神经退行性疾病，其特征是执行功能障碍和记忆障碍，由细胞外淀粉样β肽（Aβ）和细胞内过度磷酸化的tau 蛋白积累介导。海马体（HIPP）对记忆形成至关重要，并且与疾病的早期阶段有关。事实上，海马体萎缩被用作神经元损伤的早期生物标志物，并用于评估疾病进展。目前还不清楚海马体体积的变化是由于神经元还是神经胶质细胞的丢失引起的。本研究旨在使用无偏倚体视学定量评估海马体萎缩和/或神经胶质增生，并获得与神经退行性变和神经胶质增生相关的海马体蛋白质组学特征。在 AD 和非 AD 病例中进行了海马体体积测量、NeuN-、Iba-1-和 GFAP 阳性细胞的体视学定量以及连续窗口采集所有理论质谱（SWATH-MS）分析。使用 Cavalieri 探针识别到海马体体积减少，特别是在 CA1 区，其与神经元丢失和星形胶质细胞增生相关。经过基于 FC>1.5 和 值<0.01 的限制性过滤后，在 SWATH-MS 分析中鉴定出 102 个下调蛋白和 47 个上调蛋白。热休克蛋白 90 家族伴侣，特别是 BAG3 和 HSP90AB1，与星形胶质细胞密切相关，表明它们可能通过伴侣介导的自噬降解 Aβ和 tau 发挥作用。
