Astrocyte-specific loss of lactoferrin influences neuronal structure and function by interfering with cholesterol synthesis.

Growing evidence indicates that circulating lactoferrin (Lf) is implicated in peripheral cholesterol metabolism disorders. It has emerged that the distribution of Lf changes in astrocytes of aging brains and those exhibiting neurodegeneration; however, its physiological and/or pathological role remains unknown. Here, we demonstrate that astrocyte-specific knockout of Lf (designated cKO) led to decreased body weight and cognitive abnormalities during early life in mice. Accordingly, there was a reduction in neuronal outgrowth and synaptic structure in cKO mice. Importantly, Lf deficiency in the primary astrocytes led to decreased sterol regulatory element binding protein 2 (Srebp2) activation and cholesterol production, and cholesterol content in cKO mice and/or in astrocytes was restored by exogenous Lf or a Srebp2 agonist. Moreover, neuronal dendritic complexity and total dendritic length were decreased after culture with the culture medium of the primary astrocytes derived from cKO mice and that this decrease was reversed after cholesterol supplementation. Alternatively, these alterations were associated with an activation of AMP-activated protein kinase (AMPK) and inhibition of SREBP2 nuclear translocation. These data suggest that astrocytic Lf might directly or indirectly control in situ cholesterol synthesis, which may be implicated in neurodevelopment and several neurological diseases.

Novel melatonin-trientine conjugate as potential therapeutic agents for Alzheimer's disease.

Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the ß-amyloid (Aß) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aß deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aß levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology.

The human islet amyloid polypeptide reduces hippocampal tauopathy and behavioral impairments in P301S mice without inducing neurotoxicity or seeding amyloid aggregation.

Recent evidence suggests that human islet amyloid polypeptide (h-IAPP) accumulates in the brains of Alzheimer's disease (AD) patients and may interact with Aß or microtubule associated protein tau to associate with the neurodegenerative process. Increasing evidence indicates a potential protective effect of h-IAPP against Aß-induced neurotoxicity in AD mouse models. However, a direct therapeutic effect of h-IAPP supplementation on tauopathy has not been established. Here, we found that long-term h-IAPP treatment attenuated tau hyperphosphorylation levels and induced neuroinflammation and oxidative damage, prevented synaptic loss and neuronal degeneration in the hippocampus, and alleviated behavioral deficits in P301S transgenic mice (a mouse model of tauopathy). Restoration of insulin sensitization, glucose/energy metabolism, and activated BDNF signaling also contributed to the underlying mechanisms. These findings suggest that seemly h-IAPP has promise for the treatment of neurodegenerative disorders with tauopathy, such as AD.

Preparation and characterization of the ribbon-like cellulose nanocrystals by the cellulase enzymolysis of cotton pulp fibers.

The enzymolytic preparation of cellulose nanocrystals (CNCs) has the unique advantages due to its green chemistry process. In this work, the cotton pulp fibers were enzymolyzed with the cellulase to prepare the ribbon-like CNC, and the samples were characterized by SEM, FTIR, XRD and DLS. The results indicated the CNC with the length 250-900 nm and width 30-45 nm could be produced from cotton pulp fibers at the lower cellulase concentration, the time 5-11 h and temperature 50 ºC. When the cellulase concentration rose up to 100 /ml, the granular CNC appeared, and at 300 µ/ml all of the formed CNC were granular. FTIR and XRD analyses proved that the ribbon-like CNC had the same crystal style and chemical structure with original cotton pulp fibers, but its crystallinity was weakened slightly. Despite the fact that there are the weakened crystallinity and aggregates, the as-prepared samples were still called as CNCs for simplicity. In addition, the article has discussed the mechanism for the forming ribbon-like CNC from the enzymolysis of cotton pulp fibers.

Preparation and characterization of the spherical nanosized cellulose by the enzymatic hydrolysis of pulp fibers.

In this work, the pulp fibers were enzymolyzed to prepare the nanosized cellulose (NC). The as-prepared samples were characterized by optical microscopy, electron microscopy, and Raman spectra. The experimental results indicated that enzymatic hydrolysis of pulp fibers could produce the spherical NC with a mean particle size of about 30nm, which had the excellent monodispersity and uniformity. When the concentration of complex enzymes was 20u/mL (cellulase: xylanase=9: 1), the yield of NC was 13.6%. The single cellulase was used, even if the enzyme concentration reached up to 200u/mL, only a mixture of strip and granular flocculation were obtained. The positive synergistic effect between xylanase and cellulase could be due to the enzymolysis of hemicellulose located on the cellulose microfibers to be favorable of cutting and splitting of the microfibers by the endoglucanase in cellulase.