Samokhina Evgeniia, Mangat Armaan, Malladi Chandra S, Gyengesi Erika, Morley John W, Buskila Yossi
School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia.
The MARCS Institute, Western Sydney University, Penrith, New South Wales, Australia.
J Physiol. 2025 Jun;603(11):3405-3424. doi: 10.1113/JP287903. Epub 2025 May 14.
Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder characterized by neuronal loss leading to dementia and ultimately death. Whilst the loss of neurons is central to this disease, it is becoming clear that glia, specifically astrocytes, contribute to the onset and progression of neurodegeneration. The role of astrocytes in maintaining ion homeostasis in the extracellular milieu is fundamental for multiple brain functions, including synaptic plasticity and neuronal excitability, which are compromised during AD and affect neuronal signalling. In this study, we measured the astrocytic K clearance rate in the hippocampus and somatosensory cortex of a mouse model for AD during disease progression. Our results establish that astrocytic [K] (extracellular K concentration) clearance in the hippocampus is reduced in symptomatic 5xFAD mice, and this decrease is region-specific, as no significant alterations were detected in the superficial layers of the somatosensory cortex. The decrease in the [K] clearance rate correlated with a significant reduction in the expression and conductivity of Kir4.1 channels and a decline in the number of primary connected astrocytes. Moreover, astrocytes in the hippocampus of symptomatic 5xFAD mice demonstrated increased reactivity which was accompanied by an increased excitability and altered spiking profile of nearby neurons. These findings indicate that the supportive function astrocytes typically provide to nearby neurons is diminished during disease progression, which affects the neuronal circuit signalling in this area and provides a potential explanation for the increased vulnerability of neurons in AD. KEY POINTS: Astrocytic potassium clearance from the extracellular milleu is fundamental for multiple brain functions. Alterations in the clearance rate can affect the excitability and overall viability of neurons. A symptomatic mouse model for Alzheimer's disease (5xFAD) exhibits a significant decline in astrocytic K clearance at the hippocampus, but not the somatosensory cortex. The decrease in the clearance rate correlated with a reduction in the expression and conductivity of astrocytic Kir4.1 channels and a decrease in the number of primary connected astrocytes, specifically at the stratum lacunosum moleculare layer of the CA1 region. Astrocytes in the hippocampus of symptomatic 5xFAD mice displayed increased reactivity. The excitability profile and firing patterns of neurons at the hippocampus were affected by alterations in K homeostasis, indicating that the supportive function astrocytes typically provide to nearby neurons is diminished during progression of Alzheimer's disease.
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是神经元丧失，导致痴呆并最终死亡。虽然神经元丧失是这种疾病的核心，但越来越清楚的是，神经胶质细胞，特别是星形胶质细胞，在神经退行性变的发生和发展中起作用。星形胶质细胞在维持细胞外环境中离子稳态方面的作用对于多种脑功能至关重要，包括突触可塑性和神经元兴奋性，这些在AD期间会受到损害并影响神经元信号传导。在本研究中，我们在疾病进展过程中测量了AD小鼠模型海马体和体感皮层中的星形胶质细胞钾清除率。我们的结果表明，有症状的5xFAD小鼠海马体中的星形胶质细胞[K]（细胞外钾浓度）清除率降低，并且这种降低具有区域特异性，因为在体感皮层的表层未检测到明显变化。[K]清除率的降低与Kir4.1通道的表达和电导率显著降低以及初级连接星形胶质细胞数量的减少相关。此外，有症状的5xFAD小鼠海马体中的星形胶质细胞表现出反应性增加，这伴随着附近神经元的兴奋性增加和放电模式改变。这些发现表明，在疾病进展过程中，星形胶质细胞通常为附近神经元提供的支持功能减弱，这影响了该区域的神经元回路信号传导，并为AD中神经元易损性增加提供了潜在解释。要点：星形胶质细胞从细胞外环境中清除钾对于多种脑功能至关重要。清除率的改变会影响神经元的兴奋性和整体活力。阿尔茨海默病（5xFAD）的有症状小鼠模型在海马体中星形胶质细胞钾清除率显著下降，但在体感皮层中没有。清除率的降低与星形胶质细胞Kir4.1通道的表达和电导率降低以及初级连接星形胶质细胞数量的减少相关，特别是在CA1区的分子层隙状层。有症状的5xFAD小鼠海马体中的星形胶质细胞表现出反应性增加。海马体中神经元的兴奋性特征和放电模式受到钾稳态改变的影响，表明在阿尔茨海默病进展过程中，星形胶质细胞通常为附近神经元提供的支持功能减弱。
