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Biochemistry Jul 2024Munc18-1 is an SM (sec1/munc-like) family protein involved in vesicle fusion and neuronal exocytosis. Munc18-1 is known to regulate the exocytosis process by binding...
Munc18-1 is an SM (sec1/munc-like) family protein involved in vesicle fusion and neuronal exocytosis. Munc18-1 is known to regulate the exocytosis process by binding with closed- and open-state conformations of Syntaxin1, a protein belonging to the SNARE family established to be central to the exocytosis process. Our previous work studied peptide p5 as a promising drug candidate for CDK5-p25 complex, an Alzheimer's disease (AD) pathological target. Experimental and studies suggest that Munc18-1 promotes p5 to selectively inhibit the CDK5-p25 complex without affecting the endogenous CDK5 activity, a characteristic of remarkable therapeutic implications. In this paper, we identify several binding modes of p5 with Munc18-1 that could potentially affect the Munc18-1 binding with SNARE proteins and lead to off-target effects on neuronal communication using molecular dynamics simulations. Recent studies indicate that disruption of Munc18-1 function not only disrupts neurotransmitter release but also results in neurodegeneration, exhibiting clinical resemblance to other neurodegenerative conditions such as AD, causing diagnostic and treatment challenges. We characterize such interactions between p5 and Munc18-1, define the corresponding pharmacophores, and provide guidance for the validation of our findings to improve therapeutic efficacy and safety of p5.
PubMed: 38953497
DOI: 10.1021/acs.biochem.4c00148 -
Minerva Surgery Jul 2024
PubMed: 38953424
DOI: 10.23736/S2724-5691.24.10409-1 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Alzheimer's disease (AD) is a severe threat to human health and one of the three major causes of human death.Double-stranded RNA-dependent protein kinase (PKR) is an... (Review)
Review
Alzheimer's disease (AD) is a severe threat to human health and one of the three major causes of human death.Double-stranded RNA-dependent protein kinase (PKR) is an interferon-induced protein kinase involved in innate immunity.In the occurrence and development of AD,PKR is upregulated and continuously activated.On the one hand,the activation of PKR triggers an integrated stress response in brain cells.On the other hand,it indirectly upregulates the expression of β-site amyloid precursor protein cleaving enzyme 1 and facilitates the accumulation of amyloid-β protein (Aβ),which could activate PKR activator to further activate PKR,thus forming a sustained accumulation cycle of Aβ.In addition,PKR can promote Tau phosphorylation,thereby reducing microtubule stability in nerve cells.Inflammation in brain tissue,neurotoxicity resulted from Aβ accumulation,and disruption of microtubule stability led to the progression of AD and the declines of memory and cognitive function.Therefore,PKR is a key molecule in the development and progression of AD.Effective PKR detection can aid in the diagnosis and prediction of AD progression and provide opportunities for clinical treatment.The inhibitors targeting PKR are expected to control the activity of PKR,thereby controlling the progression of AD.Therefore,PKR could be a target for the development of therapeutic drugs for AD.
Topics: Alzheimer Disease; Humans; eIF-2 Kinase; Amyloid beta-Peptides; tau Proteins; Phosphorylation; Brain; Amyloid beta-Protein Precursor
PubMed: 38953267
DOI: 10.3881/j.issn.1000-503X.15792 -
Nutritional Neuroscience Jul 2024Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting approximately 55 million individuals globally. Diagnosis typically occurs in advanced... (Review)
Review
OBJECTIVES
Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting approximately 55 million individuals globally. Diagnosis typically occurs in advanced stages, and there are limited options for reversing symptoms. Preventive strategies are, therefore, crucial. Time Restricted Eating (TRE) or Time Restricted Feeding (TRF) is one such strategy. Here we review recent research on AD and TRE/TRF in addition to AD biomarkers and gut microbiota.
METHODS
A comprehensive review of recent studies was conducted to assess the impact of TRE/TRF on AD-related outcomes. This includes the analysis of how TRE/TRF influences circadian rhythms, beta-amyloid 42 (Aß42), pro-inflammatory cytokines levels, and gut microbiota composition.
RESULTS
TRE/TRF impacts circadian rhythms and can influence cognitive performance as observed in AD. It lowers beta-amyloid 42 deposition in the brain, a key AD biomarker, and reduces pro-ininflammatory cytokines. The gut microbiome has emerged as a modifiable factor in AD treatment. TRE/TRF changes the structure and composition of the gut microbiota, leading to increased diversity and a decrease in harmful bacteria.
DISCUSSION
These findings underscore the potential of TRE/TRF as a preventive strategy for AD. By reducing Aß42 plaques, modulating pro-inflammatory cytokines, and altering gut microbiota composition, TRE/TRF may slow the progression of AD. Further research is needed to confirm these effects and to understand the mechanisms involved. This review highlights TRE/TRF as a promising non-pharmacological intervention in the fight against AD.
PubMed: 38953237
DOI: 10.1080/1028415X.2024.2359868 -
ESC Heart Failure Jul 2024
PubMed: 38953155
DOI: 10.1002/ehf2.14941 -
Cureus May 2024Background The elderly population continues to grow worldwide, including in Saudi Arabia. Caring for older people with Alzheimer's and dementia disease is very...
Background The elderly population continues to grow worldwide, including in Saudi Arabia. Caring for older people with Alzheimer's and dementia disease is very challenging and merits specific skills, knowledge, and attitudes among nurses and nursing students. Consequently, nursing students must be prepared with the appropriate knowledge and attitude to care for patients affected by Alzheimer's in their future professions. This study aimed to investigate the knowledge and attitudes of Alzheimer's disease (AD) among bachelor's nursing students in Saudi Arabia. Methods This study used a descriptive cross-sectional design, and data were collected via an online questionnaire comprising two main instruments: the Alzheimer's Disease Knowledge Scale (ADKS) and the Dementia Attitudes Scale (DAS). A total of 477 undergraduate nursing students participated in the study at four universities in four regions of Saudi Arabia. Result The results indicated that Saudi nursing students exhibited insufficient knowledge regarding individuals with AD, reflected by a mean ADKS score of 13.83 out of 30. Yet, they displayed positive attitudes, as indicated by a mean DAS score of 99.29 out of 140. Nursing students in their third year and those who had family members with AD had a higher significant score regarding their knowledge of AD than nursing students who were in their fourth year or those who did not have family members who had AD. Additionally, nursing students aged 20 to 25 years, as well as nursing students in their fourth year, had more positive attitudes toward working with AD patients. Conclusions In conclusion, this study revealed that although many nursing students have a positive attitude toward working with AD patients, they have insufficient knowledge of AD. Therefore, there is an urgent necessity for enhanced educational initiatives, encompassing both greater depth and improved quality, as well as increased clinical training to address this knowledge gap among nursing students in Saudi Arabia.
PubMed: 38953079
DOI: 10.7759/cureus.61444 -
Frontiers in Plant Science 2024is a traditional Chinese herb that has gained much attention for its production of Huperzine A (HupA). HupA has shown promise on treating Alzheimer's disease (AD)....
INTRODUCTION
is a traditional Chinese herb that has gained much attention for its production of Huperzine A (HupA). HupA has shown promise on treating Alzheimer's disease (AD). However, the biosynthetic pathway and molecular mechanism of HupA in are still not well understood.
METHODS
Integrated transcriptome and metabolome analysis was performed to reveal the molecular mechanisms related to HupA biosynthesis and antioxidant activity in .
RESULTS
HT ( thallus) exhibits higher antioxidant activity and lower cytotoxicity than WH (wild ). Through hierarchical clustering analysis and qRT-PCR verification, 7 important enzyme genes and 13 transcription factors (TFs) related to HupA biosynthesis were detected. Among them, the average |logFC| value of (Cytochrome P450) and (Copper amine oxidase) was the largest. Metabolomic analysis identified 12 metabolites involved in the HupA biosynthesis and 29 metabolites related to antioxidant activity. KEGG co-enrichment analysis revealed that tropane, piperidine and pyridine alkaloid biosynthesis were involved in the HupA biosynthesis pathway. Furthermore, the phenylpropanoid, phenylalanine, and flavonoid biosynthesis pathway were found to regulate the antioxidant activity of . The study also identified seven important genes related to the regulation of antioxidant activity, including (primary-amine oxidase). Based on the above joint analysis, the biosynthetic pathway of HupA and potential mechanisms of antioxidant in was constructed.
DISCUSSION
Through differential transcriptome and metabolome analysis, DEGs and DAMs involved in HupA biosynthesis and antioxidant-related were identified, and the potential metabolic pathway related to HupA biosynthesis and antioxidant in were constructed. This study would provide valuable insights into the HupA biosynthesis mechanism and the thallus medicinal value.
PubMed: 38952843
DOI: 10.3389/fpls.2024.1411471 -
Network Neuroscience (Cambridge, Mass.) 2024[This corrects the article DOI: 10.1162/netn_a_00224.].
[This corrects the article DOI: 10.1162/netn_a_00224.].
PubMed: 38952811
DOI: 10.1162/netn_x_00380 -
Clinical Epidemiology 2024Frozen shoulder may be an early preclinical symptom of Parkinson's disease (PD).
BACKGROUND
Frozen shoulder may be an early preclinical symptom of Parkinson's disease (PD).
OBJECTIVE
To examine PD risk after frozen shoulder diagnosis and to evaluate this disorder as a possible manifestation of parkinsonism preceding the clinical recognition of PD and possible target for screening.
METHODS
Danish population-based medical registries were used to identify patients aged ≥40 years with a first-time frozen shoulder diagnosis (1995-2016). A comparison cohort was randomly selected from the general population matched on age and sex. To address detection bias and the specificity of frozen shoulder diagnosis, we performed a sensitivity analysis, using similar matching criteria to select a cohort of patients with back pain diagnosis. The outcome was incident PD. Cumulative incidences and adjusted hazard ratios (HRs) were estimated with 95% confidence intervals (CIs).
RESULTS
We identified 37,041 individuals with frozen shoulder, 370,410 general population comparators, and 111,101 back pain comparators. The cumulative incidence of PD at 0-22 years follow-up was 1.51% in the frozen shoulder cohort, 1.03% in the general population cohort, and 1.32% in the back pain cohort. For frozen shoulder versus general population, adjusted HRs were 1.94 (CI: 1.20-3.13) at 0-1 years and 1.45 (CI: 1.24-1.70) at 0-22 years follow-up. For frozen shoulder versus back pain, adjusted HRs were 0.89 (CI: 0.54-1.46) and 1.01 (CI: 0.84-1.21), respectively.
CONCLUSION
Patients with frozen shoulder had an increased PD risk compared with the general population, although the absolute risks were low. Frozen shoulder might sometimes represent early manifestations of PD. Detection bias probably cannot account for the increased PD risk during the long-term follow-up.
PubMed: 38952571
DOI: 10.2147/CLEP.S463571 -
Frontiers in Aging Neuroscience 2024Studying the spatiotemporal patterns of amyloid accumulation in the brain over time is crucial in understanding Alzheimer's disease (AD). Positron Emission Tomography...
INTRODUCTION
Studying the spatiotemporal patterns of amyloid accumulation in the brain over time is crucial in understanding Alzheimer's disease (AD). Positron Emission Tomography (PET) imaging plays a pivotal role because it allows for the visualization and quantification of abnormal amyloid beta (Aβ) load in the living brain, providing a powerful tool for tracking disease progression and evaluating the efficacy of anti-amyloid therapies. Generative artificial intelligence (AI) can learn complex data distributions and generate realistic synthetic images. In this study, we demonstrate for the first time the potential of Generative Adversarial Networks (GANs) to build a low-dimensional representation space that effectively describes brain amyloid load and its dynamics.
METHODS
Using a cohort of 1,259 subjects with AV45 PET images from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we develop a 3D GAN model to project images into a latent representation space and generate back synthetic images. Then, we build a progression model on the representation space based on non-parametric ordinary differential equations to study brain amyloid evolution.
RESULTS
We found that global SUVR can be accurately predicted with a linear regression model only from the latent representation space ( = 0.08 ± 0.01). We generated synthetic PET trajectories and illustrated predicted Aβ change in four years compared with actual progression.
DISCUSSION
Generative AI can generate rich representations for statistical prediction and progression modeling and simulate evolution in synthetic patients, providing an invaluable tool for understanding AD, assisting in diagnosis, and designing clinical trials. The aim of this study was to illustrate the huge potential that generative AI has in brain amyloid imaging and to encourage its advancement by providing use cases and ideas for future research tracks.
PubMed: 38952479
DOI: 10.3389/fnagi.2024.1410844