Molecular Mechanism of Capacitative Calcium Entry Deficits in Familial Alzheimer’s Disease

Poster PresentationPresenilin (PS) is the catalytic subunit of the gamma-secretase which is responsible for the cleavage of amyloid precursor protein to form beta amyloid (Aβ). Mutations in PS associated with familial Alzheimer’s disease (FAD) increase the Aβ plaques formation in the brain and cause neurodegeneration. Apart from this, FAD-linked PS mutations have been demonstrated to disrupt intracellular calcium (Ca2+) regulation. Accumulating evidence suggests that Ca2+ disruption may play a proximal role in the AD pathogenesis. Mutant PS exaggerated Ca2+ release from the endoplasmic reticulum (ER). It also attenuated Ca2+ entry through the capacitative Ca2+ entry (CCE) pathway, yet, the mechanism is not fully understood. Using a human neuroblast cell line SH-SY5Y and Ca2+ imaging technique, we observed CCE deficits in FAD-linked PS1-M146L retroviral infected cell. The attenuation of CCE in PS1 mutant cells was not mediated by the down-regulation of STIM1 and Orai1 expression, the known essential molecular players in the CCE pathway. Instead, we identified a molecular interaction between PS and STIM1 proteins by immunoprecipitation. On the other hand, immunofluorescence staining showed a significant reduction in puncta formation after ER Ca2+ depleted by thapsigargin in cells infected with PS1-M146L as compared to the wild type PS1 infected cells. Taken together, our results suggest a molecular mechanism for the CCE deficits in FAD associated with PS1 mutations. The interaction of mutant PS1 with STIM1 exerts a negative impact on its oligomerization and/or its interaction with Orai1. Our results may suggest molecular targets for the development of therapeutic agents that help to treat the disease.published_or_final_versio

Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

BACKGROUND Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. METHODS Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). RESULTS Positive genetic correlation was observed between MD and AD (rgMD−AD = + 0.47, P = 6.6 × 10−10). AC-quantity showed positive genetic correlation with both AD (rgAD−AC quantity = + 0.75, P = 1.8 × 10−14) and MD (rgMD−AC quantity = + 0.14, P = 2.9 × 10−7), while there was negative correlation of AC-frequency with MD (rgMD−AC frequency = −0.17, P = 1.5 × 10−10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10−6). There was no evidence for reverse causation. CONCLUSION This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Clusters of alcohol abstainers and drinkers incorporating motives against drinking: a random survey of 18 to 34 year olds in four cities in four different continents

Objective: The aim of this analysis was to identify alcohol consumption clusters for adolescents and early adults according to attitudes to drinking, motivations against drinking and perceptions associated with alcohol. Method: Interviews were undertaken with people aged 18–34 years old living in four cities in different regions of the world. Multistage random sampling was consistent across the four cities (Ilorin (Nigeria), Wuhan (China), Montevideo (Uruguay) and Moscow (Russia)). The questionnaire was forward and back translated into relevant languages and face-to-face interviewing undertaken. The data were weighted to the population of each city. In total 6235 structured interviews were undertaken (1391 in Ilorin, 1600 in Montevideo, 1604 in Moscow and 1640 in Wuhan). Questions regarding motivation against alcohol consumption (14 items), assessing perceptions (3 items) and attitudes to drinking in certain situations (8 items) were asked of all respondents including abstainers. Factor analysis was initially undertaken to identify highly related correlated variables. Results: Cluster analysis provided a variety of clusters (Ilorin (3 clusters), Montevideo (5), Moscow (4) and Wuhan (4)). At least one cluster in each city was dominated by abstainers and another by heavy episodic drinkers. Variations by city and alcohol consumption patterns existed in regards to variables included. Conclusion: This analysis detailed the city specific motivations against drinking alcohol, and the attitudes towards alcohol consumption. Differences highlight the influence of country/city specific culture, customs, laws, societal norms and traditions

Vagal Withdrawal to Sad Film Predicts Subsequent Recovery from Depression

Cardiac vagal tone, as indexed by abnormalities in the level and/or reactivity of respiratory sinus arrhythmia (RSA), has been related to psychiatric impairment, including risk for depression. Longitudinal studies of depression have focused on RSA levels and have found mixed support for the hypothesis that low RSA levels predict a more pernicious course of depression. The current investigation focuses on the relation between RSA reactivity and the course of depression. We measured depressed persons\u27 RSA reactivity to sadness‐, fear‐, and amusement‐inducing emotion films and reassessed participants\u27 diagnostic status 6 months later. Depressed persons who exhibited a higher degree of vagal withdrawal to the sad film were more likely to recover from depression. Implications for the study of RSA in depression are discussed