Cognitive impairment in Alzheimer's disease FAD4T mouse model: Synaptic loss facilitated by activated microglia via C1qA.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by cognitive dysfunction. The connection between neuroinflammation and abnormal synaptic function in AD is recognized, but the underlying mechanisms remain unclear. In this study, we utilized a mouse model of AD, FAD4T mice aged 6-7 months, to investigate the molecular changes affecting cognitive impairment. Behavior tests showed that FAD4T mice exhibited impaired spatial memory compared with their wild-type littermates. Immunofluorescence staining revealed the presence of Aß plaques and abnormal glial cell activation as well as changes in microglial morphology in the cortex and hippocampus of FAD4T mice. Synaptic function was impaired in FAD4T mice. Patch clamp recordings of hippocampal neurons revealed reduced amplitude of miniature excitatory postsynaptic currents. Additionally, Golgi staining showed decreased dendritic spine density in the cortex and hippocampus of FAD4T mice, indicating aberrant synapse morphology. Moreover, hippocampal PSD-95 and NMDAR1 protein levels decreased in FAD4T mice. RNA-seq analysis revealed elevated expression of immune system and proinflammatory genes, including increased C1qA protein and mRNA levels, as well as higher expression of TNF-α and IL-18. Taken together, our findings suggest that excessive microglia activation mediated by complement factor C1qA may contribute to aberrant synaptic pruning, resulting in synapse loss and disrupted synaptic transmission, ultimately leading to AD pathogenesis and behavioral impairments in the FAD4T mouse model. Our study provides valuable insights into the underlying mechanisms of cognitive impairments and preliminarily explores a potentially effective treatment approach targeting on C1qA for AD.

A Nano Drug Delivery System Based on Angelica sinensis Polysaccharide for Combination of Chemotherapy and Immunotherapy.

Combination of chemotherapy and immunotherapy has been a promising strategy in cancer treatment. Polysaccharides from Angelica sinensis (AP), a well-known Chinese herbal medicine, have been proved to have good immunomodulatory activity. In the present study, an enzyme-sensitive tumor-targeting nano drug delivery system (AP-PP-DOX (doxorubicin), PP stood for peptide) was constructed. In this system, Angelica polysaccharides act as not only carriers to targeted delivery of drugs to tumor tissue but also effectors to improve tumor microenvironment and enhance immune function, resulting in synergistic antitumor effect with chemotherapy drugs. The structure of this conjugate was confirmed by FI-IR and 1H-NMR. The particle size and zeta potential of the nanoparticles were 129.00 ± 3.32 nm and -28.45 ± 0.22 mV, respectively. Doxorubicin (DOX) and AP could be quickly released from the AP-PP-DOX under the presence of matrix metalloproteinase 2 (MMP2). The released DOX showed good antitumor efficacy in vitro. The treatment of released AP moiety increased the expression of IL-2, while that of IL-10 was decreased, showing potential in restoring Th1/Th2 immune balance in tumor microenvironment. In a word, this drug delivery system, with specific tissue targeting and tumor microenvironment improvement, will open a new avenue for combination treatment of cancer.

miR-320/VEGFA axis affects high glucose-induced metabolic memory during human umbilical vein endothelial cell dysfunction in diabetes pathology.

The "metabolic memory", a phenomenon that the target cell remembers the early hyperglycemia, has been reported to be a critical issue in diabetes pathogenesis. Here, we confirmed the inducible effects of high glucose (HG) and HG followed by normal glucose (HN) upon the proliferation and the tube formation capacity of human umbilical vein endothelial cells (HUVECs), as well as the suppressive effects of HG and HN on HUVEC apoptosis. In the meantime, the miR-320 expression could be dramatically downregulated (** and ## P < 0.01), whereas VEGFA expression (** and ## P < 0.01) and VEGFA, PKC, and RAGE protein levels could be remarkably induced via HG and HN stimulation. More importantly, the effects of HG and HN were not significantly different, suggesting the existence of high glucose-induced metabolic memory and the involvement of miR-320 and VEGFA in high glucose-induced metabolic memory in HUVECs. Consistently, miR-320 overexpression significantly reversed the effects of HG and HN on HUVECs (* and # P < 0.05, ** and ## P < 0.01). miR-320 suppressed the expression of VEGFA via direct binding to the 3'-UTR of VEGFA mRNA, therefore suppressing high glucose-induced metabolic memory (** P < 0.01); the effects of miR-320 overexpression on HUVECs could be reversed by VEGFA overexpression (# P < 0.05, ## P < 0.01), indicating that miR-320/VEGFA axis modulates the proliferation, apoptosis, and the angiogenesis capacity of HUVECs. In conclusion, we demonstrate that miR-320/VEGFA axis is crucial to high glucose-induced metabolic memory during HUVEC dysfunction and may be involved in the pathology of diabetes.