Dementia model mice restore function by brain rejuvenation

An international research group, led by Research Associate Masahiro Fukui and Team Director Ryoichiro Kageyama of the Laboratory for Neural Stem Cell Research at the RIKEN Center for Biosystems Dynamics Research, has successfully improved the Alzheimer's disease pathology in model mice by using a new technique for activating neural stem cells capable of differentiating into neurons and glial cells. The study is expected to contribute to the development of new treatments and the elucidation of brain aging mechanisms. The results were published in Cell Reports on April 9.

Rejuvenation of Neural Stem Cells and Improvement of Alzheimer's Disease Pathology Using iPaD.Provided by RIKEN Neurons, which play important roles in brain functions such as memory, learning and cognition, are produced from neural stem cells. Neural stem cells actively proliferate during the embryonic stage and produce a vast number of neurons to promote development of the brain.

After birth, lifelong production of new neurons called "neurogenesis" occurs in some parts of the brain, particularly in the hippocampus, where neural stem cells are activated to create new neurons which play crucial roles in learning and memory. The function of neural stem cells declines with age, which appears to be a cause of reduced neurogenesis and cognitive decline. Alzheimer's disease is a typical form of dementia, characterized by amyloid-β protein accumulation and reduced neurogenesis in the brain.

Activation of neurogenesis may improve the cognitive function. Meanwhile, previous studies have shown that temporal activation of neurogenesis does not result in a reduction of amyloid-β accumulation and a fundamental cure of the disease. It is also known that over-activation of neural stem cells causes their depletion, which leads to termination of neurogenesis itself.

In this study, the group applied the iPaD technique to aged mice to restore their functionally declined neural stem cells to a "young state". The research group developed this technique, developed in 2022. This technique activates the Plagl2 gene, which is strongly expressed in an embryonic brain, and simultaneously suppresses the Dyrk1a gene, which is strongly expressed in aged neural stem cells.

iPaD was introduced into the hippocampus of Alzheimer's disease model mice using lentivirus, and its effects on neurogenesis, amyloid-β accumulation and cognitive function were investigated. The results demonstrated that iPaD treatment markedly promoted activation of neural stem cells and production of new neurons. In the hippocampal tissue, the area covered by amyloid-β plaques, which are formed by aggregation of amyloid-β, was significantly reduced compared to the control group.

The effects were observed not only in regions in which neurogenesis actively occurs but also in surrounding regions. To further examine the effects of iPaD on cognitive function, the Barnes maze test, which evaluates spatial memory, was conducted in Alzheimer's disease model mice. By analyzing the time and distance traveled by mice until they found the exit hole among multiple holes based on memory, it was shown that activation of neurogenesis by iPaD improved the spatial memory and learning ability in mice.

Finally, to understand the mechanism of action of iPaD, they comprehensively analyzed the genes that were differentially expressed in the brains of iPaD-treated and untreated mice. As a result, they identified multiple genes, including the Prkag2 gene, which were significantly downregulated in the treated mice. Individual suppression of these genes in the hippocampus led to significant promotion of neurogenesis.

The number of immature neurons (DCX-positive cells) increased in the hippocampus in which these genes were suppressed. In addition, the area covered by amyloid-β plaques was significantly reduced. Among the genes tested, suppression of the Prkag2 gene yielded the strongest effect.

Fukui said, "This study successfully demonstrated the possibility of improving cognitive function by restoring the function of neural stem cells. As we proceeded with the experiments, we were greatly surprised and strongly encouraged when we found that activation of neurogenesis led to reduction of amyloid-β." Journal Information Publication: Cell Reports Title: Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer's disease model mice DOI: 10.

1016/j.celrep.2026.

117250 Biology Medicine 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. 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.