The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.

Scope: Decreasing β-amyloid (Aβ) accumulation is of significance in finding therapeutic candidates for cognitive impairments in Alzheimer's disease (AD). The aim of this study is to investigate the potency of the active components of walnut protein in decreasing Aβ aggregation and ameliorating cognitive impairments. Methods and results: Cell model of intracellular Aβ42 aggregation is used to explore the active ingredients in walnut protein hydrolysate (WPH). A bioactive peptide (Pro-Pro-Lys-Asn-Trp, PW5) with great anti-Aβ42 aggregation activity identified from the WPH is synthesized for in vitro and in vivo experiments. Using classic APP/PS1 mouse model, it is validated that PW5 exerts its effects on cognitive improvement through reducing Aβ plaques accumulation. Moreover, metabolomic analysis reveals that serum norepinephrine (NE) and isovalerate levels are significantly increased in response to PW5 intervention, with decreased serum levels of acetylcholine (AChe) and valerate, compared with the vehicle-treated APP/PS1 mice. PW5 feeding also improves gut dysbiosis in APP/PS1 transgenic mice by increasing the relative abundance of Firmicutes and decreasing Proteobacteria and Verrucomicrobia as displayed by 16s rRNA analyses. Conclusions: These promising results support the utilization of peptide PW5 as an active ingredient in functional foods or potential drug candidate for the prevention and/or treatment of AD.

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