Endoplasmic reticulum stress induces tau pathology and forms a vicious cycle: Implication in Alzheimer's disease pathogenesis

Accumulation of unfolded proteins can disturb the functions of the endoplasmic reticulum (ER), leading to ER-stress or unfolded protein response (UPR). Recent data have shown that activation of UPR can be found in postmortem brains of Alzheimer's disease (AD) patients; and biological markers for activation of UPR are abundant in neurons with diffuse phosphorylated tau. Although these observations suggest a linkage between ER-stress and tau pathology, little is known of their relationship. In this study, we found that high levels of phosphorylated PKR-like ER-resident kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) as markers for activation of UPR in the hippocampus of aged P301L mutant tau transgenic mice. The immunoreactivity of p-PERK was found to co-localize with that of phosphorylated tau. We then hypothesized that phosphorylation of tau could induce ER-stress and vice versa in promoting AD-like pathogenesis. By using the protein phosphatase 2A inhibitor okadaic acid (OA) as an inducer for phosphorylation of tau, we found that primary cultures of rat cortical neurons treated with OA triggered UPR as indicated by increased levels of p-PERK and p-eIF2α, splicing of mRNA for xbp-1 and elevated levels of mRNA for GADD153. On the other hand, thapsigargin as an ER-stress inducer stimulated phosphorylation of tau at Thr231, Ser262 and Ser396. Thapsigargin also induced activation of caspase-3 and cleavage of tau. These findings suggested that ER-stress and hyperphosphorylation of tau could be induced by each other to form a vicious cycle to propagate AD-like neurodegeneration. © 2012 - IOS Press and the authors. All rights reserved.postprin

Five insights from the Global Burden of Disease Study 2019

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3.5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.Peer reviewe

Dimension-based interactions with virtual assistants : a co-design project with design fictions

202207 bckwVersion of RecordSelf-fundedPublishe

The role of bedroom privacy in social interaction among elderly residents in nursing homes : an exploratory case study of Hong Kong

202011 bcrcVersion of RecordPublishe

Measuring the impact of bedroom privacy on social networks in a long-term care facility for Hong Kong older adults : a spatio-social network analysis approach

202403 bcvcVersion of RecordSelf-fundedPublishedC

Developing vestibular neurons display altered commissural projections with depletion of chondroitin sulfates of the hindbrain matrix

Chondroitin sulfate (CS) proteoglycans are involved in matrix interactions that restrict neuronal populations and their processes. To assess vestibular commissural projections in environments depleted of CS moieties, chondroitinase ABC was delivered into the 4th ventricles of rat embryos (E11.5–E13.5) in culture and DiI tracing was performed from the vestibular nuclear complex near the VIIIth cranial nerve entry zone. Enzyme treatment in E11.5 resulted in robust outgrowths that extended more than half-way towards the midline. Enzyme treatments in E12.5 and E13.5 resulted in defasciculation and divergence of outgrowths from the course of the pioneers. These results provide in vivo evidence for contributions of CS to limit stray outgrowth and foster axonal fasciculation as vestibular neurons project across the midline towards the contralateral target.link_to_subscribed_fulltex

Commissural projection from the vestibular nucleus in rat embryos: role of chondroitin sulfates

Program/Poster no. 870.6/C12To determine if chondroitin sulfates (CS) contribute restrictive guidance in commissural projections from the vestibular nucleus, we treated embryos (E12.5-14.5, Sprague-Dawley rats) with chondroitinase ABC or vehicle via the fourth ventricle for 24 hrs in culture and then tracked projections following DiI injection into the vestibular nucleus on one side. After 1 day in vitro (DIV), control treatment resulted in projections that were similar to those that developed in vivo. The projections remained fasciculated as they approached the midline (E12.5+1DIV), crossed the floor plate (E13.5+1DIV), and reached the contralateral nucleus (E14.5+1DIV). In enzyme- treated embryos, unfasciculated projections diverted from the course of the fasciculated pioneer-projections. To determine if the restrictive guidance is due to modulations in sulfation of chondroitins, we determined the mRNA expression profiles of chondroitin sulfotransferases in the hindbrains of E11.5-E16.5 embryos. Semi-quantitative RT-PCR indicated increasing expression as from E11.5 and by E13.5-14.5, peaking of the 6-sulfotransferase mRNA, leveled basal expression of the 4-sulfotransferase-1 mRNA and progressively rising 4-sulfotransferase-2 mRNA were observed. The results highlight roles of CS in fostering axonal fasciculation and limiting stray outgrowth and suggest involvement of chondroitin sulfotransferases in modulating these roles during development of vestibular commissures

Developing vestibular commissural projections display differential patterns with chondroitinase treatment of the hindbrain

Chondroitin sulfate proteoglycans have been regarded as molecules that restrict neuronal migration and neurite outgrowth. To assess the role of the chondroitin sulfate moieties on axonal projection in the hindbrain, we chose to perform DiI tracing of vestibular commissural projections following delivery of chondroitinase ABC into the 4th ventricles of rat embryos (E11.5-E13.5) in culture. At E11.5(+1DIV), few outgrowths could be traced. With enzyme treatment, robust outgrowths extended more than half-way towards the midline. At E12.5(+1DIV), the commissural projections assumed fascicles and reached the midline in the controls. In enzyme-treated embryos, the axons remained unfasciculated as they extended normal to the midline. At E13.5(+1DIV), commissural projections were fasciculated and extended beyond the midline in controls. Enzyme treatment did not affect the pioneer axons that had advanced beyond the midline and towards the contralateral vestibular nuclear complex. However, later outgrowths traversed the enzyme-treated matrix as unfasciculated fibres and diverted from the course of the pioneers. These results provide in vivo evidence for contributions of chondroitin sulfates not only to restrict initial axonal sprouts, but also to limit later axonal outgrowths and to foster axonal fasciculation as vestibular neurons project across the midline towards the contralateral target. Supported by HKRG