Alzheimer’s disease (AD), a predominant neurodegenerative disorder, is clinically characterized by progressive cognitive deterioration and behavioral deficits. An in-depth understanding of the pathogenesis and neuropathology of AD is essential for the development of effective treatments and early diagnosis techniques. The neuropathological signature of AD involves two hallmark lesions: intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau aggregates and extracellular senile plaques containing amyloid-β (Aβ) peptide depositions. Although Aβ-centric research has dominated AD investigations over the past three decades, pharmacological interventions targeting Aβ pathology have failed to demonstrate clinical efficacy. Tau, a microtubule-associated protein predominantly localized to neuronal axons, orchestrates microtubule stabilization and axonal transport through dynamic tubulin interactions under physiological conditions. In AD pathogenesis, however, tau undergoes pathogenic post-translational modifications (PTMs), encompassing hyperphosphorylation, lysine acetylation, methylation, ubiquitination, and glycosylation. These PTM-driven alterations induce microtubule network disintegration, mitochondrial dysfunction, synaptic impairment, and neuroinflammatory cascades, ultimately culminating in irreversible neurodegeneration and progressive cognitive decline. This review synthesizes contemporary advances in tau PTM research and delineates their mechanistic contributions to AD pathogenesis, thereby establishing a framework for biomarker discovery, targeted therapeutic development, and precision medicine approaches in tauopathies. This review synthesizes contemporary advances in tau PTM research and delineates their mechanistic contributions to AD pathogenesis, thereby establishing a solid theoretical and experimental basis for the early diagnosis of neurodegenerative diseases, the discovery of therapeutic targets, and the development of novel therapeutic strategies.

JOURNAL/nrgr/04.03/01300535-202404000-00038/inline-graphic1/v/2023-09-09T133047Z/r/image-tiff Proteolytic cleavage of tau by asparagine endopeptidase (AEP) creates tau-N368 fragments, which may drive the pathophysiology associated with synaptic dysfunction and memory deterioration in the brain of Alzheimer’s disease patients. Nonetheless, the molecular mechanisms of truncated tau-induced cognitive deficits remain unclear. Evidence suggests that signal transduction and activator of transcription-3 (STAT3) is associated with modulating synaptic plasticity, cell apoptosis, and cognitive function. Using luciferase reporter assays, electrophoretic mobility shift assays, western blotting, and immunofluorescence, we found that human tau-N368 accumulation inhibited STAT3 activity by suppressing STAT3 translocation into the nucleus. Overexpression of STAT3 improved tau-N368-induced synaptic deficits and reduced neuronal loss, thereby improving the cognitive deficits in tau-N368 mice. Moreover, in tau-N368 mice, activation of STAT3 increased N-methyl-D-aspartic acid receptor levels, decreased Bcl-2 levels, reversed synaptic damage and neuronal loss, and thereby alleviated cognitive deficits caused by tau-N368. Taken together, STAT3 plays a critical role in truncated tau-related neuropathological changes. This indicates a new mechanism behind the effect of tau-N368 on synapses and memory deficits. STAT3 can be used as a new molecular target to treat tau-N368-induced protein pathology.

Field surveys over the past two decades have established that Tetranychus truncatus has become the dominant spider mite pest on major crops in China, including corn, cotton, soybean, eggplant, and cucumber. Notably, these populations exhibit a widespread infection with the endosymbiont Wolbachia. Despite its invasion into China in the late 20th century, the globally notorious Tetranychus urticae has failed to replace T. truncatus in these host plants. We sought to elucidate the molecular mechanisms underlying the dominant status of T. truncatus in China through a multi-disciplinary approach encompassing genomic evolution, population genetics, transcriptional regulation, and symbiont-host interactions. A high-quality, chromosome-level genome assembly of T. truncatus was constructed using the third-generation sequencing technology (PacBio) and Hi-C scaffolding. To analyze population structure and gene flow across China, whole-genome resequencing was performed on 343 individuals from 44 field populations. Transcriptional plasticity was evaluated through host-transfer experiments combined with comparative transcriptomic analysis to measure responses of multiply populations of T. truncatus and T. urticae when feeding on diverse plants. Furthermore, small RNA sequencing and RNAi were performed to investigate the cross-kingdom regulatory effects of Wolbachia-derived small non-coding RNAs (sncRNAs) on host reproduction. The results reveal that the expansion of gene families involved in detoxification (e.g., P450s, GSTs, UGTs) and chemosensation provides the genetic foundation for the polyphagy of T. truncatus. These gene families exhibit high levels of transcriptomic plasticity when the spider mites adapt to diverse hosts, although the overall plasticity level in T. truncatusis lower than that of T. urticae. Nevertheless, both spider mites utilize the same core detoxification enzymes to adapt to corresponding hosts, enabling rapid responses to various plant defensive stresses. Furthermore, Wolbachia-derived small non-coding RNAs (sncRNAs) were found to specifically target host mRNA, significantly enhancing the oviposition of T. truncatus and achieving symbiont-driven reproductive promotion and fitness compensation. Finally, population genomic analysis reveals prominent long-distance, cross-regional gene flow within northern T. truncatus populations, indicating that human activities may bridge geographic barriers and facilitate the rapid dispersal of resistance alleles. In conclusion, the ecological dominance of T. truncatus is orchestrated by a synergy of strong detoxification capacity, high transcriptional plasticity, symbiont-mediated reproductive gains, and human-promoted dispersal.