Chicote-González Almudena, Solana-Balaguer Júlia, Garcia-Segura Pol, Campoy-Campos Genís, Pérez Inés Pérez, Pérez-Navarro Esther, Rodríguez Manuel J, Alberch Jordi, Giralt Albert, Soria Guadalupe, Malagelada Cristina
Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Catalonia, Spain.
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
Alzheimers Dement. 2025 Apr;21(4):e70051. doi: 10.1002/alz.70051.
Alzheimer's disease (AD) pathogenesis involves astrocytic responses to extracellular amyloid beta deposits and phospho-tau neurofibrillary tangles, which drive inflammatory activation. RTP801, a stress-responsive protein, has been implicated in mediating neuroinflammation. Its levels are increased in AD hippocampal samples, correlating with disease severity and cognitive decline.
Using astrocyte-specific RTP801 silencing in the hippocampus of 5xFAD mice, we evaluated cognition, neuroinflammation, and hippocampal connectivity by magnetic resonance spectroscopy (MRS) and resting-state functional connectivity analyses. Histological and biochemical analyses assessed microgliosis, astrogliosis, and inflammasome-related protein levels.
Astrocytic RTP801 silencing in 5xFAD mice preserved spatial memory, maintained hippocampal γ-aminobutyric acid (GABA) levels, and preserved resting-state brain networks. In addition, RTP801 silencing significantly reduced markers of microgliosis, astrogliosis, and inflammasome effectors.
Astrocytic RTP801 contributes to AD-associated cognitive decline by disrupting GABAergic-regulated connectivity and amplifying inflammatory responses. Targeting astrocytic RTP801 may therefore offer therapeutic potential to mitigate AD progression by preserving neural connectivity and reducing neuroinflammation.
The 5xFAD mouse model of Alzheimer's disease presents higher levels of RTP801 in hippocampal astrocytes. Normalizing the levels of astrocytic RTP801 prevents cognitive decline and restores anxiety-like behavior in the 5xFAD mouse model. Knocking down astrocytic RTP801 preserves the resting-state functional connectivity in the 5xFAD mouse model. Astrocytic RTP801 mediates the loss of Parvalbumin+ interneurons, negatively affecting the levels of γ-aminobutyric acid (GABA) in the 5xFAD mouse model. Astrocytic RTP801 contributes to astro- and microgliosis and inflammasome expression in the 5xFAD mouse model.
阿尔茨海默病（AD）的发病机制涉及星形胶质细胞对细胞外淀粉样β沉积和磷酸化tau神经原纤维缠结的反应，这些反应会引发炎症激活。RTP801是一种应激反应蛋白，与介导神经炎症有关。其在AD海马样本中的水平升高，与疾病严重程度和认知能力下降相关。
我们在5xFAD小鼠的海马中使用星形胶质细胞特异性RTP801沉默技术，通过磁共振波谱（MRS）和静息态功能连接分析来评估认知、神经炎症和海马连接性。组织学和生化分析评估了小胶质细胞增生、星形胶质细胞增生以及炎性小体相关蛋白水平。
在5xFAD小鼠中沉默星形胶质细胞RTP801可保留空间记忆，维持海马γ-氨基丁酸（GABA）水平，并保留静息态脑网络。此外，RTP801沉默显著降低了小胶质细胞增生、星形胶质细胞增生和炎性小体效应物的标志物。
星形胶质细胞RTP801通过破坏GABA能调节的连接性和放大炎症反应，导致与AD相关的认知能力下降。因此，靶向星形胶质细胞RTP801可能具有治疗潜力，通过保留神经连接性和减少神经炎症来减轻AD的进展。
阿尔茨海默病的5xFAD小鼠模型在海马星形胶质细胞中呈现出较高水平的RTP801。使星形胶质细胞RTP801水平正常化可预防5xFAD小鼠模型中的认知能力下降并恢复类似焦虑的行为。敲低星形胶质细胞RTP801可保留5xFAD小鼠模型中的静息态功能连接性。星形胶质细胞RTP801介导小白蛋白阳性中间神经元的丧失，对5xFAD小鼠模型中的γ-氨基丁酸（GABA）水平产生负面影响。星形胶质细胞RTP801在5xFAD小鼠模型中促成星形胶质细胞和小胶质细胞增生以及炎性小体表达。
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