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Background: Mitochondrial dysfunction (MD) is increasingly recognized as a key pathophysiological contributor in Alzheimer disease (AD). As differential MD genes expression may serve as either a causative factor or a consequence in AD, and expression of these genes could be influenced by epigenetic modifications or interact with inflammatory cytokines, hence, the precise role of MD in AD remains uncertain. Methods: Meta-analysis of brain transcriptome datasets was conducted to pinpoint differentially expressed genes (DEGs) associated with MD in AD. We utilized three-step SMR to analyze the AD genome-wide association study summaries with expression quantitative trait loci (eQTLs) and DNA methylation QTLs from the blood and brain tissues, respectively. Through SMR and colocalization analysis, we further explored the interactions between brain eQTLs and inflammatory cytokines. Results: Five datasets were meta-analyzed to prioritize 825 DEGs in AD from 1339 MD-related genes. Among these, seven genes from blood samples such as NDUFS8 and SPG7 and thirty-two genes from brain tissue including CLU and MAPT were identified as candidate AD-causal MD genes and regulated by methylation level. Furthermore, we revealed 13 MD gene expression-inflammatory pathway pairs involving LDLR, ACE and PTPMT1 along with interleukin-17C, interleukin-18 and hepatocyte growth factor. Conclusions: This study highlighted that the AD-causal MD genes could be regulated by epigenetic changes and interact with inflammatory cytokines, providing evidence for AD prevention and intervention. [ABSTRACT FROM AUTHOR]

Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear. Objective: We summarized the current evidence from several aspects and further quantified these associations. Methods: We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression. Results: Of 9,267 identified literatures, 23 were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer's disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI) = 1.21–1.65) and a 1.57-fold excess risk for AD (95% CI = 1.15–2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CI = 1.19–1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearity = 0.0000) and AD (pnonlinearity = 0.0042). The approximate 77.5–100 nmol/L 25-hydroxyvitamin D [25(OH)D] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level >40.1 nmol/L. Conclusions: Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention. [ABSTRACT FROM AUTHOR]

Bistable composite structures have a wide application prospect in the design of deformable structures. In this study, the snap behaviors of unsymmetric cross-ply bistable composites with different thicknesses are investigated. Besides the experiments, the relationships between load and displacement during the snap process are also analyzed by finite element (FE) methods. The load-displacement curves of composite shell with four layers and two layers are completely different. The results of the two-layer cylindrical shell with resin layer are in good agreement with the experimental results. The resin layer has great influence on the snap behaviors of the two-layer bistable cylindrical shell, although it has little effect on the four-layer cylindrical shell. So it cannot be ignored in the analyzing of two-layer bistable shell. The cause of experimental errors is also analyzed. The research results of this paper have reference value for the engineering design of bistable composite structures. [ABSTRACT FROM AUTHOR]

Background: Extracellular free water (FW) resulting from white matter degeneration limits the sensitivity of diffusion tensor imaging (DTI) in predicting Alzheimer's disease (AD)., Purpose: To evaluate the sensitivity of FW-DTI in detecting white matter microstructural changes in AD. To validate the effectiveness of FW-DTI indices to predict amyloid-beta (Aβ) positivity in mild cognitive impairment (MCI) subtypes., Study Type: Retrospective., Population: Thirty-eight Aβ-negative cognitively healthy (CH) controls (68.74 ± 8.28 years old, 55% female), 15 Aβ-negative MCI patients (MCI-n) (68.87 ± 8.83 years old, 60% female), 29 Aβ-positive MCI patients (MCI-p) (73.03 ± 7.05 years old, 52% female), and 29 Aβ-positive AD patients (72.93 ± 9.11 years old, 55% female)., Field Strength/sequence: 3.0T; DTI, T 1 -weighted, T 2 -weighted, T 2 star-weighted angiography, and Aβ PET ( 18 F-florbetaben or 11 C-PIB)., Assessment: FW-corrected and standard diffusion indices were analyzed using trace-based spatial statistics. Area under the curve (AUC) in distinguishing MCI subtypes were compared using support vector machine (SVM)., Statistical Tests: Chi-squared test, one-way analysis of covariance, general linear regression analyses, nonparametric permutation tests, partial Pearson's correlation, receiver operating characteristic curve analysis, and linear SVM. A P value <0.05 was considered statistically significant., Results: Compared with CH/MCI-n/MCI-p, AD showed significant change in tissue compartment indices of FW-DTI. No difference was found in the FW index among pair-wise group comparisons (the minimum FWE-corrected P = 0.114). There was a significant association between FW-DTI indices and memory and visuospatial function. The SVM classifier with tissue radial diffusivity as an input feature had the best classification performance of MCI subtypes (AUC = 0.91), and the classifying accuracy of FW-DTI was all over 89.89%., Data Conclusion: FW-DTI indices prove to be potential biomarkers of AD. The classification of MCI subtypes based on SVM and FW-DTI indices has good accuracy and could help early diagnosis., Evidence Level: 4 TECHNICAL EFFICACY: Stage 2., (© 2023 International Society for Magnetic Resonance in Medicine.)