A research group including Assistant Professor Jun Tsuyama and Professor Takashi Shichita of the Department of Neuroinflammation and Repair at the Medical Research Laboratory, Institute of Integrated Research at the Institute of Science Tokyo, in collaboration with the Tokyo Metropolitan Institute of Medical Science (TMiMS), Kyushu University, and the University of Freiburg (Germany), has clarified the mechanism by which brain tissue damaged by a stroke shows temporary recovery through rehabilitation. The team revealed that a protein called ZFP384 is the factor responsible for terminating this recovery power. They also confirmed that recovery can be sustained using an antisense oligonucleotide that suppresses this protein. The achievement is expected to lead to the development of therapeutic drugs that reduce aftereffects. The results were published in Nature on May 13.
In Japan, stroke is a common condition among the elderly aged 65 and older, ranking as the fourth leading cause of death and the primary cause of becoming bedridden. Cerebral infarction, which accounts for 80% of strokes, occurs when blood vessels in the brain are blocked by blood clots, causing tissue necrosis and often leaving significant aftereffects. Currently, no therapeutic drugs exist to promote recovery after this stage.
It is known that brain function declines for about a week following the onset of a cerebral infarction (acute phase). Function can be partially restored following this through rehabilitation and other means (recovery phase), but this recovery power is subsequently lost (chronic phase). On the other hand, the mechanism that halts this recovery power after the functional decline remained unknown.
If this mechanism could be clarified, it might be possible to sustain the recovery power. Therefore, the research group focused on microglia, the immune cells of the brain. Neurotrophic factors such as insulin-like growth factor 1 (IGF1) secreted by microglia function to reconstruct synapses and repair myelin sheaths.
First, to investigate the function of microglia during the recovery phase of cerebral infarction, the research team observed mice expressing fluorescence in IGF1 gene-expressing cells before and after cerebral infarction. They found that while IGF1-expressing microglia were rarely present before the infarction, they increased rapidly on the sixth day after the cerebral infarction.
Next, when examining the total gene expression of only the microglia expressing the IGF1 gene in detail, they found that these cells produced large amounts of various factors involved in brain repair. Furthermore, the team used gene editing to develop mice from which IGF1-producing microglia could be removed and eliminated these microglia after a cerebral infarction. As a result, the mice lacking IGF1-producing microglia showed greater worsening of neurological symptoms after the cerebral infarction.
This revealed that IGF1-producing microglia actively facilitate brain recovery. However, this recovery power disappears after the recovery phase. Therefore, the researchers tracked the IGF1-producing microglia until one month after the cerebral infarction, when the recovery phase ends.
The results confirmed that the microglia around the cerebral infarction lesion that had been producing IGF1 ceased production after one month but remained in the same location. This was also true for microglia producing repair factors other than IGF1.
To clarify the cause of this production, the team searched for transcription factors operating one month after the onset of cerebral infarction that affect YY1, a transcription factor that induces microglia to produce neurotrophic factors, and investigated their functions. The results showed that TGFβ, a protein that increases when the brain attempts to return to its pre-damaged state during the chronic phase of cerebral infarction, acts on microglia, thereby increasing the transcription factor ZFP384.
They discovered that ZFP384 causes YY1 to detach from the DNA, rendering the microglia unable to produce neurotrophic factors.
When they developed mice incapable of producing ZFP384 in microglia and observed them after cerebral infarction, they confirmed that the recovery of neurological symptoms was sustained.
The team then considered developing an antisense oligonucleotide that acts on and inhibits only this specific gene.
Having successfully developed an antisense oligonucleotide that inhibits ZFP384, they administered it into the brain ventricles of cerebral infarction mice on either the 8th day or the 1st month after onset. As a result, neurological symptoms improved compared to mice with cerebral infarction that did not receive either treatment. This revealed that recovery power is maintained even one month after onset.
Analysis of brain tissue from deceased patients who had suffered cerebral infarctions also confirmed that numerous IGF1-producing microglia were present in the brain one week after onset, decreasing over the period of one to two months post-onset.
Tsuyama stated: "We believe this achievement will lead to the realization of medical care that does not give up on functional recovery after a stroke and can eliminate aftereffects. We also hope to popularize the therapeutic concept of 'sustaining the recovery power inherent in organs.'"
Shichita stated: "Even if it takes 10 or 20 years, we wish to continue our efforts to ensure this therapeutic drug reaches patients."
Journal Information
Publication: Nature
Title: Sustaining microglial reparative function enhances stroke recovery
DOI: 10.1038/s41586-026-10480-0
This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.