Endosomal-lysosomal dysfunctions in Alzheimer's disease: Pathogenesis and therapeutic interventions.

The endosomal-lysosomal system mediates the process of protein degradation through endocytic pathway. This system consists of early endosomes, late endosomes, recycling endosomes and lysosomes. Each component in the endosomal-lysosomal system plays individual crucial role and they work concordantly to ensure protein degradation can be carried out functionally. Dysregulation in the endosomal-lysosomal system can contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). In AD endosomal-lysosomal abnormalities are the earliest pathological features to note and hence it is important to understand the involvement of endosomal-lysosomal dysfunction in the pathogenesis of AD. In-depth understanding of this dysfunction can allow development of new therapeutic intervention to prevent and treat AD.

Pseudoginsenoside-F11 attenuates cerebral ischemic injury by alleviating autophagic/lysosomal defects.

AIMS: Pseudoginsenoside-F11 (PF11), an ocotillol-type ginsenoside, has been reported to exert wide-ranging neuroprotective properties. The aim of this study was to investigate the effect and potential mechanisms of PF11 on the autophagic/lysosomal pathway following ischemic stroke. METHODS: Male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (pMCAO). Cerebral ischemia outcome, TUNEL staining, Fluoro-Jade B staining were carried out 24 hours poststroke. The autophagic/lysosomal-related proteins were measured. RESULTS: A single administration of PF11 significantly decreased the infarct area, reduced the brain water content, and improved neurological functions, even 4 hours after the onset of pMCAO. Meanwhile, PF11 lessened the ischemic insult-mediated loss of neurons and activation of astrocytes and microglia. Furthermore, PF11 attenuated pMCAO-induced accumulations of autophagosomes and apoptosis. We further observed a remarkable effect of PF11 in reversing the ischemic insult-induced accumulation of autophagosomes (LC3-II) and abnormal aggregation of autophagic proteins (SQSTM1 and ubiquitin). Furthermore, PF11 was capable of improving lysosomal function and lysosome/autophagosome fusion following pMCAO, and this change was reversed by the lysosomal inhibitor chloroquine. Also, the improvement of ischemic outcome and the antiapoptotic effect induced by PF11 was reversed by CQ. CONCLUSION: These findings indicate that the autophagic flux is impaired in a rat model of pMCAO, and that PF11 exerts an excellent protective effect against ischemic stroke by alleviating autophagic/lysosomal defects.

Brain trauma and autophagy: What flies and mice can teach us about conserved responses.

Drosophila models have been successfully used to identify many genetic components that affect neurodegenerative disorders. Recently, there has been a growing interest in identifying innate and environmental factors that influence the individual outcomes following traumatic brain injury (TBI). This includes both severe TBI and more subtle, mild TBI (mTBI), which is common in people playing contact sports. Autophagy, as a clearance pathway, exerts protective effects in multiple neurological disease models. In a recent publication, we highlighted the development of a novel repetitive mTBI system using Drosophila, which recapitulates several phenotypes associated with trauma in mammalian models. In particular, flies subjected to mTBI exhibit an acute impairment of the macroautophagy/autophagy pathway that is restored 1 wk following traumatic injury exposure. These phenotypes closely resemble temporary autophagy defects observed in a mouse TBI model. Through these studies, we also identified methods to directly assess autophagic responses in the fly nervous system and laid the groundwork for future studies designed to identify genetic, epigenetic and environmental factors that have an impact on TBI outcomes.