Maternal cardiovascular health in early pregnancy and the risk of congenital heart defects in offspring.

BACKGROUND: Congenital heart disease (CHD) is the predominant birth defect. This study aimed to explore the association between maternal cardiovascular health (CVH) and the CHD risk in offspring. METHODS: We used the prospective data from the Fujian Birth Cohort Study, collected from March 2019 to December 2022 on pregnant women within 14 weeks of gestation. Overall maternal CVH was assessed by seven CVH metrics (including physical activity, smoking, sleep duration, body mass index, blood pressure, total cholesterol, and fasting plasma glucose), with each metric classified as ideal, intermediate or poor with specific points. Participants were further allocated into high, moderate and low CVH categories based on the cumulative CVH score. The association with offspring CHD was determined with log-binominal regression models. RESULTS: A total of 19810 participants aged 29.7 (SD: 3.9) years were included, with 7846 (39.6%) classified as having high CVH, 10949 (55.3%) as having moderate CVH, and 1015 (5.1%) as having low CVH. The average offspring CHD rate was 2.52%, with rates of 2.35%, 2.52% and 3.84% across the high, moderate and low CVH categories, respectively (P = 0.02). Adjusted relative risks (RRs) of having offspring CHD were 0.64 (95% CI: 0.45-0.90, P = 0.001) for high CVH and 0.67 (95% CI: 0.48-0.93, P = 0.02) for moderate CVH compared to low CVH. For individual metrics, only ideal total cholesterol was significantly associated with lower offspring CHD (RR: 0.73, 95% CI: 0.59-0.83, P = 0.002). CONCLUSIONS: Pregnant women of high or moderate CVH categories in early pregnancy had reduced risks of CHD in offspring, compared to those of low CVH. It is important to monitor and improve CVH during pre-pregnancy counseling and early prenatal care.

Nitrogen balance and outcomes in critically ill patients: A systematic review and meta-analysis.

Objective: Nitrogen balance (NB) is a commonly used nutrition indicator in clinical practice, while its relation to the interpretation of protein malnutrition and outcomes in critically ill patients remains unclear. This study aimed to evaluate the impact of NB on prognosis in such a patient population. Methods: We searched for relevant studies in PubMed, EMBASE, and the Cochrane Database up to May 10, 2022. Meta-analyses were performed to evaluate the relationship between NB (initial, final, or absolute change of NB levels) and prognosis and important clinical outcomes in critically ill patients. Pooled odds ratios (ORs) and mean differences (MDs) together with their 95% confidence intervals (CIs) were calculated. We also conducted subgroup analyses to explore the sources of heterogeneity. Results: Eight studies with 1,409 patients were eligible. These studies were moderate to high quality. When pooled, the initial NB was comparable between the survival and non-survival groups (five studies, MD 1.20, 95% CI, -0.70 to 3.11, I 2 = 77%; P = 0.22), while a significantly higher final NB in the survival group than that in the death group (two studies, MD 3.69, 95% CI, 1.92-5.46, I 2 = 55%; P < 0.0001). Two studies provided the absolute change of NB over time and suggested survival patients had more increased NB (MD 4.16 g/day, 95% CI, 3.70-4.61, I 2 = 0%; P < 0.00001). Similarly, for studies utilizing multivariate logistic regression, we found an improved NB (four studies, OR 0.85, 95% CI, 0.73-0.99, I 2 = 61%; P = 0.04) but not an initial NB (two studies, OR 0.92, 95% CI 0.78-1.08, I 2 = 55%; P = 0.31) was significantly associated the risk of all-cause mortality. These results were further confirmed in subgroup analyses. In addition, patients with improved NB had more protein and calorie intake and a similar length of stay in hospital than those without. Conclusions: Our results suggested that an improved NB but not the initial NB level was associated with all-cause mortality in critically ill patients. This highlights the requirement for dynamic monitoring of NB during nutrition treatment. Further randomized clinical trials examining the impact of NB-guided protein intake on clinical outcomes in critically ill patients are warranted. Systematic review registration: INPLASY202250134, https://doi.org/10.37766/inplasy2022.5.0134.

Awake prone positioning for patients with COVID-19 pneumonia in intensive care unit: A systematic review and meta-analysis.

Background: Awake prone positioning (APP) has been widely used in non-intubated COVID-19 patients during the pandemic. However, high-quality evidence to support its use in severe COVID-19 patients in an intensive care unit (ICU) is inadequate. Therefore, we aimed to assess the efficacy and safety of APP for intubation requirements and other important outcomes in this patient population. Methods: We searched for potentially relevant articles in PubMed, Embase, and the Cochrane database from inception to May 25, 2022. Studies focusing on COVID-19 adults in ICU who received APP compared to controls were included. The primary outcome was the intubation requirement. Secondary outcomes were mortality, ICU stay, and adverse events. Study quality was independently assessed, and we also conducted subgroup analysis, sensitivity analysis, and publication bias to explore the potential influence factors. Results: Ten randomized controlled trials with 1,686 patients were eligible. The quality of the included studies was low to moderate. Overall, the intubation rate was 35.2% in the included patients. The mean daily APP duration ranged from <6 to 9 h, with poor adherence to APP protocols. When pooling, APP significantly reduced intubation requirement (risk ratio [RR] 0.84; 95%CI, 0.74-0.95; I 2 = 0%, P = 0.007). Subgroup analyses confirmed the reduced intubation rates in patients who were older (≥60 years), obese, came from a high mortality risk population (>20%), received HFNC/NIV, had lower SpO2/FiO2 (<150 mmHg), or undergone longer duration of APP (≥8 h). However, APP showed no beneficial effect on mortality (RR 0.92 [95% CI 0.77-1.10; I 2 = 0%, P = 0.37] and length of ICU stay (mean difference = -0.58 days; 95% CI, -2.49 to 1.32; I 2 = 63%; P = 0.55). Conclusion: APP significantly reduced intubation requirements in ICU patients with COVID-19 pneumonia without affecting the outcomes of mortality and ICU stay. Further studies with better APP protocol adherence will be needed to define the subgroup of patients most likely to benefit from this strategy.

Targeted Temperature Management for Cardiac Arrest Due to Non-shockable Rhythm: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Targeted temperature management (TTM) is recommended in adult patients following cardiac arrest (CA) with any rhythm. However, as to non-shockable (NSR) CA, high-quality evidence of TTM supporting its practices remains uncertain. Thus, we aimed to conduct a systematic review and meta-analysis with randomized controlled trials (RCTs) to explore the efficacy and safety of TTM in this population. Methods: We searched PubMed, Embase, and Cochrane library databases for potential trials from inception through Aug 25, 2021. RCTs evaluating TTM for CA adults due to NSR were included, regardless of the timing of cooling initiation. Outcome measurements were mortality and good neurological function. We used the Cochrane bias tools to evaluate the quality of the included studies. Heterogeneity, subgroup analyses, and sensitivity analysis were investigated to test the robustness of the primary outcomes. Results: A total of 14 RCTs with 4,009 adults were eligible for the final analysis. All trials had a low to moderate risk of bias. Of the included trials, six compared NSR patients with or without TTM, while eight compared pre-hospital to in-hospital TTM. Pooled data showed that TTM was not associated with improved mortality (Risk ratio [RR] 1.00; 95% CI, 0.944-1.05; P = 0.89, I 2 = 0%) and good neurological outcome (RR 1.18; 95% CI 0.90-1.55; P = 0.22, I 2 = 8%). Similarly, use of pre-hospital TTM resulted in neither an improved mortality (RR 0.99, 95% CI 0.97-1.03; I 2 = 0%, P = 0.32) nor favorable neurological outcome (RR 1.13, 95% CI 0.93-1.38; I 2 = 0%, P = 0.22). These results were further confirmed in the sensitivity analyses and subgroup analyses. Conclusions: Our results showed that using the TTM strategy did not significantly affect the mortality and neurologic outcomes in CA survival presenting initial NSR.

Serum creatinine/cystatin C ratio as a muscle mass evaluating tool and prognostic indicator for hospitalized patients: A meta-analysis.

Objective: Sarcopenia is a syndrome of decreased muscle mass and deficits in muscle strength and physical function. We aimed to investigate the relationship between creatinine/cystatin C ratio (CCR) and sarcopenia and the prognostic value of CCR in hospitalized patients. Materials and methods: We searched for relevant studies in PubMed, EMBASE, and the Cochrane Database up to August 25, 2022. Meta-analyses were performed to evaluate the relationship between CCR and skeletal muscle [computed tomography-assessed skeletal muscle (CTASM), muscle strength, and physical performance], prognosis and important clinical outcomes in hospitalized adults. The pooled correlation coefficient, the area under the receiver operating characteristic (ROC) curves, and hazard ratio (HR) together with their 95% confidence intervals (CIs) were calculated. We also conducted subgroup analyses to explore the sources of heterogeneity. Results: A total of 38 studies with 20,362 patients were eligible. These studies were of moderate to high quality. Our results showed that CCR was significant correlations with all CTASM types (Fisher's Z ranged from 0.35 to 0.5; P values ranged from < 0.01 to 0.01), handgrip strength (Fisher's Z = 0.39; 95% CI, 0.32-0.45; P < 0.001) and gait speed (Fisher's Z = 0.25; 95% CI, 0.21-0.30; P < 0.001). The ROC curves suggested that CCR had good diagnostic efficacy (0.689; 95% CI, 0.632-0.746; P < 0.01) for sarcopenia. CCR can reliably predict mortality in hospitalized patients, which was confirmed by regression analysis of CCR as both continuous (HR 0.78; 95% CI, 0.72-0.84; P < 0.01) and categorical variables (HR 2.05; 95% CI, 1.58-2.66; P < 0.0001). In addition, less evidence showed that higher CCR was independently associated with a shorter duration of mechanical ventilation, reduced length of stay in the intensive care unit and hospital, less nutritional risk, and decreased complications in hospitalized patients. Conclusion: CCR could be a simple, economical, and effective screening tool for sarcopenia in hospitalized patients, and it is a helpful prognostic factor for mortality and other important clinical outcomes. Systematic review registration: https://inplasy.com/inplasy-2022-9-0097/, identifier INPLASY202290097.

A Machine Learning-Based Prediction of Hospital Mortality in Patients With Postoperative Sepsis.

Introduction: The incidence of postoperative sepsis is continually increased, while few studies have specifically focused on the risk factors and clinical outcomes associated with the development of sepsis after surgical procedures. The present study aimed to develop a mathematical model for predicting the in-hospital mortality among patients with postoperative sepsis. Materials and Methods: Surgical patients in Medical Information Mart for Intensive Care (MIMIC-III) database who simultaneously fulfilled Sepsis 3.0 and Agency for Healthcare Research and Quality (AHRQ) criteria at ICU admission were incorporated. We employed both extreme gradient boosting (XGBoost) and stepwise logistic regression model to predict the in-hospital mortality among patients with postoperative sepsis. Consequently, the model performance was assessed from the angles of discrimination and calibration. Results: We included 3,713 patients who fulfilled our inclusion criteria, in which 397 (10.7%) patients died during hospitalization, and 3,316 (89.3%) patients survived through discharge. Fluid-electrolyte disturbance, coagulopathy, renal replacement therapy (RRT), urine output, and cardiovascular surgery were important features related to the in-hospital mortality. The XGBoost model had a better performance in both discriminatory ability (c-statistics, 0.835 vs. 0.737 and 0.621, respectively; AUPRC, 0.418 vs. 0.280 and 0.237, respectively) and goodness of fit (visualized by calibration curve) compared to the stepwise logistic regression model and baseline model. Conclusion: XGBoost model has a better performance in predicting hospital mortality among patients with postoperative sepsis in comparison to the stepwise logistic regression model. Machine learning-based algorithm might have significant application in the development of early warning system for septic patients following major operations.

Clinical Efficiency of Vasopressin or Its Analogs in Comparison With Catecholamines Alone on Patients With Septic Shock: A Systematic Review and Meta-Analysis.

BACKGROUND: Vasopressin is an efficient remedy for septic shock patients as its great capacity in promoting hemodynamic stabilization. The aim of current systematic review and meta-analysis is to compare the clinical efficiency of vasopressin or its analogs with sole catecholamines on patients with septic shock. METHODS: A systematic search of Cochrane Library, EMBASE, and PubMed online databases was performed up to 30 Oct 2019 to identify randomized controlled trials comparing use of vasopressin or its analogs (e.g., terlipressin, selepressin) with administration of catecholamines alone. RESULTS: We included 23 RCTs with 4,225 patients in the current study. Compared with solely use of catecholamines, administration of vasopressin or its analogs was not associated with reduced 28-day or 30-day mortality among patients with septic shock [RR=0.94 (95% CI, 0.87-1.01), P=0.08, I2 = 0%]. The result of primary endpoint remained unchanged after conducting sensitivity analysis. Despite a significantly higher risk of digital ischemia in patients receiving vasopressin or its analogs [RR=2.65 (95% CI, 1.26-5.56), P < 0.01, I2 = 48%], there was no statistical significance in the pooled estimate for other secondary outcomes, including total adverse events, arrhythmia, acute myocardial infarction (AMI) and cardiac arrest, acute mesenteric ischemia, ICU/hospital length of stay, and mechanical ventilation (MV) duration. CONCLUSIONS: The administration of vasopressin or its analogs was not associated with reduced 28-day or 30-day mortality among patients with septic shock, while an increased incidence of digital ischemia should be noted in patients receiving agonists for vasopressin receptors.

Is intensive glucose control bad for critically ill patients? A systematic review and meta-analysis.

Background: The monitoring and management of blood glucose concentration are standard practices in critical settings as hyperglycaemia has been shown close association with poorer outcomes. Several meta-analyses have revealed that intensive glucose control has no benefit in decreasing short-term mortality among critically ill patients, while the studies these meta-analyses have incorporated have been largely divergent. We aim to perform a more comprehensive meta-analysis addressing this problem to provide stronger evidence. Methods: We conducted comprehensive searches for relevant randomized controlled studies in online databases, including the Cochrane Library, EMBASE, and PubMed databases, up to September 1, 2018. The clinical data, which included all-cause mortality, severe hypoglycemia, need for RRT, infection resulting in sepsis, ICU mortality, 90-day mortality, 180-day mortality, and hospital and ICU lengths of stay, were screened and analyzed after data extraction. We applied odds ratios (ORs) to analyze dichotomous outcomes and mean differences for continuous outcomes with a random effects model. Results: A total of 57 RCTs involving a total of 21840 patients were finally included. Patients admitted to the ICU who underwent intensive glucose control showed significantly reduced all-cause mortality (OR: 0.89; 95% CI: 0.80-1.00; P=0.04; I2=32%), reduced infection rate (OR: 0.65, 95% CI: 0.51-0.82, P=0.0002; I2=47%), a lower occurrence of acquired sepsis (OR: 0.80, 95% CI: 0.65-0.99, P=0.04; I2=0%) and shortened length of ICU stay (MD: -0.70, 95% CI: -1.21--0.19, P=0.007, I2=70%) when compared to the same parameters as those treated with the usual care strategy. However, patients in the intensive glucose control group presented with a significantly higher risk of severe hypoglycemia (OR: 5.63, 95% CI: 4.02-7.87, P<0.00001; I2=67%). Conclusions: Critically ill patients undergoing intensive glucose control showed significantly reduced all-cause mortality, length of ICU stay and incidence of acquired infection and sepsis compared to the same parameters in patients treated with the usual care strategy, while the intensive glucose control strategy was associated with higher occurrence of severe hypoglycemic events.

Is haemoglobin below 7.0 g/dL an optimal trigger for allogenic red blood cell transfusion in patients admitted to intensive care units? A meta-analysis and systematic review.

OBJECTIVES: We employed a comprehensive systematic review and meta-analysis to assess benefits and risks of a threshold of haemoglobin level below 7 g/dL versus liberal transfusion strategy among critically ill patients, and even patients with septic shock. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We performed systematical searches for relevant randomised controlled trials (RCTs) in the Cochrane Library, EMBASE and PubMed databases up to 1 September 2019. ELIGIBILITY CRITERIA: RCTs among adult intensive care unit (ICU) patients comparing 7 g/dL as restrictive strategy with liberal transfusion were incorporated. DATA EXTRACTION AND SYNTHESIS: The clinical outcomes, including short-term mortality, length of hospital stay, length of ICU stay, myocardial infarction (MI) and ischaemic events, were screened and analysed after data collection. We applied odds ratios (ORs) to analyse dichotomous outcomes and standardised mean differences (SMDs) to analyse continuous outcomes with fixed or random effects models based on heterogeneity evaluation for each outcome. RESULTS: Eight RCTs with 3415 patients were included. Compared with a more liberal threshold, a red blood cell (RBC) transfusion threshold <7 g/dL haemoglobin showed no significant difference in short-term mortality (OR: 0.90, 95% CI: 0.67 to 1.21, p=0.48, I2=53%), length of hospital stay (SMD: -0.11, 95% CI: -0.30 to 0.07, p=0.24, I2=71%), length of ICU stay (SMD: -0.03, 95% CI: -0.14 to 0.08, p=0.54, I2=0%) or ischaemic events (OR: 0.80, 95% CI: 0.43 to 1.48, p=0.48, I2=51%). However, we found that the incidence of MI (OR: 0.54, 95% CI: 0.30 to 0.98, p=0.04, I2=0%) was lower in the group with the threshold <7 g/dL than that with the more liberal threshold. CONCLUSIONS: An RBC transfusion threshold <7 g/dL haemoglobin is incapable of decreasing short-term mortality in ICU patients according to currently published evidences, while it might have potential role in reducing MI incidence.

Multiple MicroRNAs Ameliorate Hepatocyte Steatosis and Injury by Suppressing FABP1 Expression.

BACKGROUND/AIMS: Liver fatty acid-binding protein (FABP1) is a key regulator of hepatic lipid metabolism. MicroRNAs (miRNAs) are thought to be involved in nonalcoholic fatty liver disease (NAFLD), and the underlying mechanism is largely unclear. We investigated whether miRNAs influence hepatocyte steatosis by regulating the FABP1 gene. METHODS: Candidate FABP1-targeting miRNAs were evaluated using luciferase reporter assay. FABP1 expression was measured using western blotting and quantitative reverse transcription-PCR. Intracellular lipid accumulation was measured based on Oil Red O staining and intracellular triglyceride content. Hepatocyte injury was evaluated based on culture supernatant levels of alanine aminotransferase, aspartate aminotransferase, and intracellular adenosine triphosphate, and mitochondrial membrane potential. RESULTS: Dicer1 knockdown significantly elevated FABP1 expression. In total, 68 miRNAs potentially targeting FABP1 were selected; of these, miR-3941, miR-4517, and miR-4672 directly targeted the FABP1 3' untranslated region. Mimics of the three miRNAs substantially repressed FABP1 expression at translational level and led to HepG2 cell resistance to steatosis and cell injury induced by free fatty acids mixture, which rescue of FABP1 overexpression reversed. CONCLUSION: Our findings identify a novel mechanism by which miRNAs protect against hepatocyte steatosis and injury by downregulating FABP1 expression.

Hepatitis B Virus X Protein Induces Hepatic Steatosis by Enhancing the Expression of Liver Fatty Acid Binding Protein.

UNLABELLED: Hepatitis B virus (HBV) has been implicated as a potential trigger of hepatic steatosis although molecular mechanisms involved in the pathogenesis of HBV-associated hepatic steatosis still remain elusive. Our prior work has revealed that the expression level of liver fatty acid binding protein 1 (FABP1), a key regulator of hepatic lipid metabolism, was elevated in HBV-producing hepatoma cells. In this study, the effects of HBV X protein (HBx) mediated FABP1 regulation on hepatic steatosis and the underlying mechanism were determined. mRNA and protein levels of FABP1 were measured by quantitative RT-PCR (qPCR) and Western blotting. HBx-mediated FABP1 regulation was evaluated by luciferase assay, coimmunoprecipitation, and chromatin immunoprecipitation. Hepatic lipid accumulation was measured by using Oil-Red-O staining and the triglyceride level. It was found that expression of FABP1 was increased in HBV-producing hepatoma cells, the sera of HBV-infected patients, and the sera and liver tissues of HBV-transgenic mice. Ectopic overexpression of HBx resulted in upregulation of FABP1 in HBx-expressing hepatoma cells, whereas HBx abolishment reduced FABP1 expression. Mechanistically, HBx activated the FABP1 promoter in an HNF3ß-, C/EBPα-, and PPARα-dependent manner, in which HBx increased the gene expression of HNF3ß and physically interacted with C/EBPα and PPARα. On the other hand, knockdown of FABP1 remarkably blocked lipid accumulation both in long-chain free fatty acids treated HBx-expressing HepG2 cells and in a high-fat diet-fed HBx-transgenic mice. Therefore, FABP1 is a key driver gene in HBx-induced hepatic lipid accumulation via regulation of HNF3ß, C/EBPα, and PPARα. FABP1 may represent a novel target for treatment of HBV-associated hepatic steatosis. IMPORTANCE: Accumulating evidence from epidemiological and experimental studies has indicated that chronic HBV infection is associated with hepatic steatosis. However, the molecular mechanism underlying HBV-induced pathogenesis of hepatic steatosis still remains to be elucidated. In this study, we found that expression of liver fatty acid binding protein (FABP1) was dramatically increased in the sera of HBV-infected patients and in both sera and liver tissues of HBV-transgenic mice. Forced expression of HBx led to FABP1 upregulation, whereas knockdown of FABP1 remarkably diminished lipid accumulation in both in vitro and in vivo models. It is possible that HBx promotes hepatic lipid accumulation through upregulating FABP1 in the development of HBV-induced nonalcoholic fatty liver disease. Therefore, inhibition of FABP1 might have therapeutic value in steatosis-associated chronic HBV infection.

Association of a Human FABP1 Gene Promoter Region Polymorphism with Altered Serum Triglyceride Levels.

Liver fatty acid-binding protein (L-FABP), also known as fatty acid-binding protein 1 (FABP1), is a key regulator of hepatic lipid metabolism. Elevated FABP1 levels are associated with an increased risk of cardiovascular disease (CVD) and metabolic syndromes. In this study, we examine the association of FABP1 gene promoter variants with serum FABP1 and lipid levels in a Chinese population. Four promoter single-nucleotide polymorphisms (SNPs) of FABP1 gene were genotyped in a cross-sectional survey of healthy volunteers (n = 1,182) from Fuzhou city of China. Results showed that only the rs2919872 G>A variant was significantly associated with serum TG concentration(P = 0.032).Compared with the rs2919872 G allele, rs2919872 A allele contributed significantly to reduced serum TG concentration, and this allele dramatically decreased the FABP1 promoter activity(P < 0.05). The rs2919872 A allele carriers had considerably lower serum FABP1 levels than G allele carriers (P < 0.01). In the multivariable linear regression analysis, the rs2919872 A allele was negatively associated with serum FABP1 levels (ß = -0.320, P = 0.003), while serum TG levels were positively associated with serum FABP1 levels (ß = 0.487, P = 0.014). Our data suggest that compared with the rs2919872 G allele, the rs2919872 A allele reduces the transcriptional activity of FABP1 promoter, and thereby may link FABP1 gene variation to TG level in humans.

Increased axonal mitochondrial mobility does not slow amyotrophic lateral sclerosis (ALS)-like disease in mutant SOD1 mice.

Reduced axonal mitochondrial transport has been observed in major neurodegenerative diseases, including fALS patients and SOD1(G93A) mice. However, it is unclear whether this defect plays a critical role in axonal degeneration or simply reflects sequelae of general transport alteration. Using genetic mouse models combined with time-lapse imaging of live neurons, we previously discovered that axon-targeted syntaphilin (SNPH) acts as a docking receptor specific for axonal mitochondria. Deletion of the snph gene in mice results in a substantially higher proportion of axonal mitochondria in the mobile state without any effect on the transport of other axonal organelles. Here we address whether increased (rescued) axonal mitochondrial mobility changes the disease course by crossing fALS-linked transgenic SOD1(G93A) and snph(-/-) knock-out mice. We found that a 2-fold increase in axonal mitochondrial mobility in SOD1(G93A)/snph(-/-) mice did not affect the onset of ALS-like symptoms. Both SOD1(G93A) and SOD1(G93A)/snph(-/-) mice exhibit similar weight loss, deterioration in motor function and motor neuron loss, significant gliosis, and a lifespan of 152-154 days. Thus, for the first time, our study provides genetic and pathological evidence that the impairment of mitochondrial transport seen in SOD1(G93A) mice plays a minimal role in the rapid-onset of fALS-linked pathology.

Snapin deficiency is associated with developmental defects of the central nervous system.

The autophagy-lysosomal pathway is an intracellular degradation process essential for maintaining neuronal homoeostasis. Defects in this pathway have been directly linked to a growing number of neurodegenerative disorders. We recently revealed that Snapin plays a critical role in co-ordinating dynein-driven retrograde transport and late endosomal-lysosomal trafficking, thus maintaining efficient autophagy-lysosomal function. Deleting snapin in neurons impairs lysosomal proteolysis and reduces the clearance of autolysosomes. The role of the autophagy-lysosomal system in neuronal development is, however, largely uncharacterized. Here, we report that snapin deficiency leads to developmental defects in the central nervous system. Embryonic snapin-/- mouse brain showed reduced cortical plates and intermediate zone cell density, increased apoptotic death in the cortex and third ventricle, enhanced membrane-bound LC3-II staining associated with autophagic vacuoles and an accumulation of polyubiquitinated proteins in the cortex and hippocampus. Thus our results provide in vivo evidence for the essential role of late endocytic transport and autophagy-lysosomal function in maintaining neuronal survival and development of the mammalian central nervous system. In addition, our study supports the existence of a functional interplay between the autophagy-lysosome and ubiquitin-proteasome systems in the protein quality-control process.

Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons.

Neuron maintenance and survival require late endocytic transport from distal processes to the soma where lysosomes are predominantly localized. Here, we report a role for Snapin in attaching dynein to late endosomes through its intermediate chain (DIC). snapin(-/-) neurons exhibit aberrant accumulation of immature lysosomes, clustering and impaired retrograde transport of late endosomes along processes, reduced lysosomal proteolysis due to impaired delivery of internalized proteins and hydrolase precursors from late endosomes to lysosomes, and impaired clearance of autolysosomes, combined with reduced neuron viability and neurodegeneration. The phenotypes are rescued by expressing the snapin transgene, but not the DIC-binding-defective Snapin-L99K mutant. Snapin overexpression in wild-type neurons enhances late endocytic transport and lysosomal function, whereas expressing the mutant defective in Snapin-DIC coupling shows a dominant-negative effect. Altogether, our study highlights new mechanistic insights into how Snapin-DIC coordinates retrograde transport and late endosomal-lysosomal trafficking critical for autophagy-lysosomal function, and thus neuronal homeostasis.

[A new hypothesis for early pathogenesis in Alzheimer's disease: impaired axonal transport mechanism].

Alzheimer's disease (AD) is characterized by amyloid beta (Abeta) plaques and neurofibrillary tangles in the brain, reduced synaptic density, and progressive neuronal dysfunction and loss. The elevated levels of the Abeta peptides in brain likely associated to neurodegeneration and cognitive and behavioral abnormalities. While such amyloid mechanism contributes to Alzheimer's pathological conditions, recent studies from a number of laboratories suggest that defective axonal transport may represent an early stage in AD pathogenesis because axonal swellings and reduced axonal transport were observed before apparent AD hallmarks. Here, we overview recent findings that could compromise neuronal abnormalities and provide molecular and cellular insights into the potential mechanisms underlying the defective axonal transport. We also discuss issues to be addressed in future in elucidation of the complex cellular events involved in AD pathogenesis.