Why Memory Deteriorates After Stroke?

Post-stroke cognitive impairment presents with diverse and often insidious symptoms. Memory decline is the most common manifestation, wherein patients exhibit difficulty recalling recent events, such as a recently consumed meal or a newly encountered individual; in severe cases, they may even forget personal identity information or daily routines. Some patients develop language expression difficulties, characterized by anomia, paraphasias, repetitive speech, or an inability to articulate complete thoughts.

On June 21, 2025, Professor Yi Xie and Professor Xinfeng Liu from Nanjing University School of Medicine published research in Cell Reports titled: "Lipocalin-2 regulates astrocyte-oligodendrocyte interaction to drive post-stroke secondary demyelination." Their study reveals that Lipocalin-2 (LCN2) drives post-stroke secondary demyelination by regulating the interaction between astrocytes and oligodendrocytes.

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Overview

The specific involvement of oligodendrocytes in this process has remained ill-defined. To elucidate this, a distal middle cerebral artery occlusion (dMCAO) model was established in mice. By seven days post-injury, Lipocalin-2 (LCN2) was observed to partially disseminate from the infarct-adjacent corpus callosum into the contralateral hemisphere. Concurrently, in reactive astrocytes of the contralateral corpus callosum, LCN2 exhibited significant upregulation at both transcriptional and translational levels.

Further investigation elucidated that PERK-mediated endoplasmic reticulum stress drove the activation of these contralateral astrocytes, leading to their autonomous synthesis of LCN2. Subsequently, mature oligodendrocytes internalized this LCN2, which precipitated the degeneration of their cellular processes and induced apoptosis. Astrocyte-specific knockout of the Lcn2 gene attenuated oligodendrocyte loss, demyelination, and cognitive dysfunction after cerebral infarction; conversely, astrocyte-specific overexpression of LCN2 reversed these beneficial effects. Mechanistic studies indicated that this LCN2-induced myelin damage likely involves a physical interaction with low-density lipoprotein receptor-related protein 2 (LRP2) on oligodendrocytes, which then activates the JNK3 signaling pathway. Specific knockdown of Lrp2 ameliorated LCN2-induced oligodendrocyte damage.

The authors' findings demonstrate that reactive astrocytes regulate post-stroke secondary demyelination via the LCN2-LRP2 signaling pathway, uncovering a novel intercellular pathogenic axis. This provides crucial insights into the mechanisms of white matter injury after cerebral infarction and offers a potential direction for developing targeted therapeutic strategies.

Findings of the Study

In summary, the authors have elucidated the mechanism of interaction between astrocytes and oligodendrocytes during distal white matter injury following focal ischemic stroke. Their findings demonstrate that modulating this intercellular communication can effectively mitigate demyelination. Specifically, endoplasmic reticulum stress, sensed by PERK, prompts reactive astrocytes to release substantial amounts of Lipocalin-2 (LCN2) extracellularly. Subsequently, mature oligodendrocytes internalize LCN2 via the expression of low-density lipoprotein receptor-related protein 2 (LRP2), which in turn activates the JNK3/c-Jun signaling pathway, leading to oligodendrocyte dysfunction or even apoptosis. This research provides a theoretical basis and potential interventional strategies for treating neurovascular diseases involving white matter lesions, by targeting either secreted LCN2 or its downstream receptor LRP2.

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Reference

1. Huang, Zhenqian et al. "Lipocalin-2 regulates astrocyte-oligodendrocyte interaction to drive post-stroke secondary demyelination." Cell reports, vol. 44,7 115899. 21 Jun. 2025, doi:10.1016/j.celrep.2025.115899. Distributed under Open Access license CC BY 4.0, without modification.