Alzheimer's disease (AD) is characterized by cognitive decline and the accumulation of amyloid-beta plaques and hyperphosphorylated tau protein. The role of tau lactylation at the K677 site in AD progression is not well understood. This study explores how tau K677 lactylation affects ferritinophagy, ferroptosis, and their functions in an AD mouse model. Results show that mutating the K677 site to R reduces tau lactylation and inhibits ferroptosis by regulating iron metabolism factors like NCOA4 and FTH1.Tau-mutant mice showed improved memory and learning skills compared to wild-type mice. The mutation also reduced neuronal damage and was associated with decreased tau lactylation at the K677 site, regardless of phosphorylated tau levels. Gene set enrichment analysis showed that lactylation at this site was linked to the MAPK pathway, which was important for ferritinophagy in AD mice. In summary, our research indicates that the K677 mutation in tau protein may protect against AD by influencing ferritinophagy and ferroptosis through MAPK signaling pathways. Understanding these modifications in tau could lead to new treatments for AD.

Background: Fine-scale genetic structure of ethnolinguistically diverse Chinese populations can fill the gap in the missing diversity and evolutionary landscape of East Asians, particularly for anthropologically informed Chinese minorities. Hmong–Mien (HM) people were one of the most significant indigenous populations in South China and Southeast Asia, which were suggested to be the descendants of the ancient Yangtze rice farmers based on linguistic and archeological evidence. However, their deep population history and biological adaptative features remained to be fully characterized.Objectives: To explore the evolutionary and adaptive characteristics of the Miao people, we genotyped genome-wide SNP data in Guizhou HM-speaking populations and merged it with modern and ancient reference populations via a comprehensive population genetic analysis and evolutionary admixture modeling.Results: The overall genetic admixture landscape of Guizhou Miao showed genetic differentiation between them and other linguistically diverse Guizhou populations. Admixture models further confirmed that Miao people derived their primary ancestry from geographically close Guangxi Gaohuahua people. The estimated identity by descent and effective population size confirmed a plausible population bottleneck, contributing to their unique genetic diversity and population structure patterns. We finally identified several natural selection candidate genes associated with several biological pathways.Conclusions: Guizhou Miao possessed a specific genetic structure and harbored a close genetic relationship with geographically close southern Chinese indigenous populations and Guangxi historical people. Miao people derived their major ancestry from geographically close Guangxi Gaohuahua people and experienced a plausible population bottleneck which contributed to the unique pattern of their genetic diversity and structure. Future ancient DNA from Shijiahe and Qujialing will provide new insights into the origin of the Miao people.

Background: Yungui Plateau in Southwest China is characterized by multi-language and multi-ethnic communities and is one of the regions with the wealthiest ethnolinguistic, cultural and genetic diversity in East Asia. There are numerous Tai-Kadai (TK)-speaking populations, but their detailed evolutionary history and biological adaptations are still unclear.Results: Here, we genotyped genome-wide SNP data of 77 unrelated TK-speaking Zhuang and Dong individuals from the Yungui Plateau and explored their detailed admixture history and adaptive features using clustering patterns, allele frequency differentiation and sharing haplotype patterns. TK-speaking Zhuang and Dong people in Guizhou are closely related to geographically close TK and Hmong-Mien (HM)-speaking populations. Besides, we identified that Guizhou TK-speaking people have a close genetic relationship with Austronesian (AN)-speaking Atayal and Paiwan people, which is supported by the common origin of the ancient Baiyue tribe. We additionally found subtle genetic differences among the newly studied TK people and previously reported Dais via the fine-scale genetic substructure analysis based on the shared haplotype chunks. Finally, we identified specific selection candidate signatures associated with several essential human immune systems and neurological disorders, which could provide evolutionary evidence for the allele frequency distribution pattern of genetic risk loci.Conclusions: Our comprehensive genetic characterization of TK people suggested the strong genetic affinity within TK groups and extensive gene flow with geographically close HM and Han people. We also provided genetic evidence that supported the common origin hypothesis of TK and AN people. The best-fitted admixture models further suggested that ancestral sources from northern millet farmers and southern inland and coastal people contributed to the formation of the gene pool of the Zhuang and Dong people.

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal mortality and disability, yet effective treatments remain limited. Gastrodia elata is a Chinese medicinal herb that has both medicinal and edible properties. Previous studies have shown that gastrodin has neuroprotective potential for brain injury. There is currently no clear evidence proving that gastrodin is toxic to newborns. Gastrodin may be a promising drug for treating HIE. To investigate this, a hypoxic-ischemic brain damage (HIBD) model in neonatal rats was established, followed by an immediate intraperitoneal injection of gastrodin injection. The model was validated using laser speckle contrast imaging, and brain tissue damage was assessed using hematoxylin–eosin (H&E) staining, Nissl staining and 2,3,5-triphenyltetrazolium chloride (TTC) staining. Neurobehavioral evaluations were conducted and Western blotting and ELISA were used to analyze oxidative stress and inflammatory cytokine levels in brain tissue. Additionally, an oxygen–glucose deprivation/reperfusion (OGD/R) injury model was created using SH-SY5Y cells, which were treated with gastrodin injection immediately following the induction of injury. The P62-specific inhibitor XRK3F2 was then used to examine the neuroprotective mechanisms of gastrodin injection in more detail. Cell viability, intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential and oxidative stress-related proteins were then measured. The results showed that gastrodin injection significantly reduced the volume of cerebral infarction in HIBD rats, alleviated oxidative stress-induced neuronal damage and improved short- and long-term neurobehavioral deficits. Gastrodin injection also enhanced mitochondrial function, boosted antioxidant capacity, and attenuated neuroinflammation. In the OGD/R model, gastrodin injection increased neuronal survival, suppressed oxidative stress and inhibited apoptosis. However, these neuroprotective effects were partially reversed by XRK3F2, a P62 inhibitor. This study suggests that gastrodin injection may reduce oxidative stress and apoptosis, thereby improving the outcome of brain injury following HIBD. This study shows that gastrodin injections could improve the outcome for rats with HIBD, possibly by activating the P62/Nrf2/HO-1 pathway; it should be noted that this study neither validated direct interactions between proteins nor employed direct counting for neuronal survival rates. Additionally, the long-term effects on the nervous system were not examined at the protein level. These areas represent directions for future research requiring further refinement.