Pseudoginsenoside-F11 alleviates oligomeric ß-amyloid-induced endosome-lysosome defects in microglia.

Amyloid accumulation in the brain is the major pathological hallmark of Alzheimer disease (AD). Amyloid beta (Aß) is cleared by the endosomal-autophagy-lysosomal system, which is impaired in AD pathogenesis by an unknown mechanism. Pseudoginsenoside-F11 (PF11), an ocotillol-type ginsenoside, has been demonstrated to decrease the level of Aß in APP/PS1 mouse brain and to protect neurons by inhibiting the activation of microglia in vitro. The present study showed that PF11 was capable of increasing the uptake and degradation of oligomeric Aß in cultured microglia. Oligomeric Aß (oAß) interrupted the autophagy-lysosomal degradative system by regulating the nuclear translocation of transcription factor EB (TFEB), a master factor in lysosomal biogenesis. Conversion of Rab5 to Rab7, which is important for the mechanism of cargo progression from early to late endosomes, was also interrupted by high-concentration oAß. Notably, in the PF11-treated microglial cells, a dramatic increase of the lysosome-associated proteins and enzyme expression were observed, along with the intracellular pH steady state, indicating the improvement of lysosomal function. In addition, PF11 induced TFEB nuclear translocation in microglia treated with high-concentration oAß. Furthermore, PF11 was able to restore Rab conversion, suggesting an effective role of PF11 in the maturation of endosomes. These data provide evidence that PF11 can reverse the dysfunction of the endosomal-lysosomal system induced by high-concentration oAß in microglia, and this might be the main mechanism by which PF11 facilitates oAß clearance. Accordingly, we propose that PF11 should be considered as a potential agent for treating AD.

Prospective study on a novel treatment for leaking cystic bleb: Efficacy and safety of collagen crosslinking.

IMPORTANCE: Management of cystic bleb leak is difficult. It would be essential to look for a method to strengthen the original pathological conjunctiva and reverse bleb leak. BACKGROUND: To evaluate the long-term efficacy and safety of collagen crosslinking in patients with leaking cystic bleb. DESIGN: Prospective interventional case series at a university-based hospital. PARTICIPANTS: Twelve eyes in 12 subjects with late-onset bleb leak from cystic bleb, without indications for prompt surgical interventions were included. METHODS: The subjects underwent crosslinking with 0.1% riboflavin application to bleb surface, followed by ultraviolet irradiation for 30 minutes. The subjects were followed up at baseline and at 1 week, 1 month, 3 months, 6 months post-treatment and then every 6 months afterwards. MAIN OUTCOME MEASURES: Interval from treatment to cessation of bleb leak, recurrence rate of bleb leak and side effects of treatment. RESULTS: The mean follow-up after crosslinking was 29.33 ± 12.45 months. Bleb leak subsided in 11 (92%) of 12 patients after a single session of crosslinking, after 1 to 8 weeks (median 3 weeks). Time to leak cessation was significantly correlated with the number of prior glaucoma interventions (R = .71, P = .014). Bleb wall at 3 months was significantly thicker than at baseline (0.70 ± 0.67 vs 0.81 ± 0.62 mm, P = .008). None of the patients experienced any complications. CONCLUSIONS AND RELEVANCE: Crosslinking achieves resolution of cystic bleb leak which lasts for at least 12 months, without the need of subsequent surgical interventions. Crosslinking is a simple, non-invasive treatment for bleb leak. It aims to restore the integrity of conjunctiva.