Current Alzheimer research最新文献

Background: Prolonged or repeated psychological stress triggers dental and orthodontic diseases via inflammatory pathways and oxidative stress. This review aims to elucidate the role of inflammation, gut microbiota, stress, and cognition, exploring their impact on the development of therapeutics to enhance oral health.

Objective: The primary aim pertinent to this systematic review is to elucidate the significant implications of cognition and stress in dental and orthodontic health. Specifically, the review aims to (1) investigate the association between emotional stress and the incidence or progression of periodontal disease; (2) explore the impact of physiological and emotional stress on cellular and molecular inflammatory responses in orthodontics; (3) examine the influence of gut-mediated psychophysiological factors on emotional changes in mental health and cognition with a focus on periodontics and orthodontics; and (4) investigate the potential of gut microbiota alterations to influence oral and cognitive/mental health, including the impact of probiotic supplementation and dietary interventions.

Methods: A systematic review was conducted without comprehensive meta-analysis, focusing on literature from 1960 to 2024. Databases searched included PubMed, Embase, ReleMed, National Library of Medicine (NLM), Scopus, and Google Scholar. Keywords used were "cognition," "emotional stress," "gut microbiota," "orthodontics," "prosthetics," "pathophysiology," and "mental health." Studies were selected based on relevance, publication date, access to full texts, and adherence to PRISMA guidelines. The review integrated findings on the impact of emotional stress on periodontal disease and orthodontic health through pathophysiological implications.

Results: Age-related neurodegeneration causes Alzheimer's disease and severe dementia that subsequently promotes poor oral health. The review identified a complex interplay between emotional stress and periodontal disease. While a direct association remains to be conclusively proven, several studies highlight the influence of stress on the severity and incidence of periodontal disease through inflammatory and immunological pathways. Stress manifests in various ways, such as increased masticatory muscle tone, changes in eating behavior, and the initiation of bruxism, all of which can affect dental health. Physiological stress induces an inflammatory response to orthodontic tooth movement, impacting orthodontic treatment outcomes. Furthermore, the review elucidates the role of gut-mediated psychophysiological factors in emotional changes, influencing periodontal and orthodontic health. Emerging evidence suggests that gut microbiota alterations can significantly impact oral and cognitive health through systemic inflammation and neuroimmune mechanisms.

Conclusion: This review highlights the significant impa

Aim: This study aims to investigate the molecular mechanisms underlying Alzheimer's disease (AD) by analyzing differentially expressed miRNAs and their target proteins to identify key regulatory networks and therapeutic targets.

Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder with multifaceted regulatory mechanisms involving differentially expressed miRNAs. Recent studies suggest that understanding the target proteins of these miRNAs may reveal crucial insights into AD pathology.

Objective: The objective of this study was to investigate the role of differentially expressed miRNAs in Alzheimer's disease (AD) by identifying their target proteins and exploring the associated regulatory networks. This includes uncovering key hub proteins and their involvement in critical biological pathways linked to AD progression. Additionally, the study aims to identify transcription factors regulating these proteins and evaluate potential therapeutic compounds targeting these molecular players. By integrating these findings, the research seeks to provide a deeper understanding of AD pathogenesis and pave the way for novel therapeutic strategies to mitigate its progression.

Methods and materials: Differentially expressed miRNAs were collected from reviews, with target proteins identified using MiRDB, STRING, and Cytoscape. Promoter and transcription factor (TF) analyses were performed using Enrichr, and potential therapeutic compounds targeting hub proteins were explored via DrugBank.

Results: This study identifies key hub proteins, including TNF, PTEN, KRAS, ESR1, H3-3B, COL25A1, COL19A1, COL13A1, COL27A1, COL5A3, CCND1, FGF2, SMAD2, and PXDN, exploring their roles in AD progression. GO and KEGG pathway analyses revealed that hub proteins, including TNF, PTEN, KRAS, and ESR1, are involved in essential biological processes related to neural differentiation and signaling. Cytocluster analysis identified clusters with significant associations with AD, indicating complex interaction networks among these proteins.

Discussion: Potential therapeutic agents, including TNF inhibitors, estrogen receptor agonists, and KRAS inhibitors, were identified. Promoter and TF analysis further highlighted regulatory factors in AD pathways.

Conclusion: This study emphasizes crucial AD-related proteins and pathways, providing insights for future therapeutic targeting of gene expression to mitigate AD progression.

Introduction: Behavioral and Psychological Symptoms of Dementia (BPSD) pose significant challenges for individuals with dementia and their caregivers. Agitation symptoms, in particular, present a complex management dilemma as there is a lack of consensus regarding pharmacotherapy, specifically with respect to the controversial use of valproate formulations. This study aims to assess the effectiveness of valproate treatment in addressing BPSD, with a specific focus on managing agitation symptoms in individuals with dementia.

Methods: A retrospective analysis was conducted at Peking Union Medical College Hospital (PUMCH) on patients diagnosed with BPSD who received valproate formulations between 2013 and 2023. Patients were classified into 'effective,' 'ineffective,' and 'unknown' groups based on their response to valproate treatment, and the distribution of BPSD symptoms between the effective and ineffective groups was compared.

Results: Among the 116 patients studied, 62.1% exhibited effective responses, 12.1% showed ineffectiveness, and 25.9% had uncertain outcomes with valproate therapy. While the effective group displayed a higher prevalence of agitation symptoms and other behaviors like wandering, restricted and repetitive behaviors, and sleep disturbances compared to the ineffective group, these differences did not reach statistical significance (p = 0.156, 1.000, 0.899, 0.283). Patients in the ineffective group were more likely to experience aggression with comorbid psychotic symptoms compared to those in the effective group (p = 0.023).

Discussion: Valproate may benefit agitation-predominant BPSD without psychosis. Discrepancies in prior findings may stem from differing dosing strategies. Its limited efficacy in psychosis-related aggression underscores the need for careful clinical evaluation.

Conclusion: The findings suggest that tailored valproate treatment at low doses may be beneficial in managing agitation without psychosis in Asian BPSD patients. Further validation through randomized controlled trials is essential to substantiate these observations.

Social isolation (SI) and loneliness (perceived social isolation) are considered as risk factors for developing dementia, including Alzheimer's disease (AD), in the elderly population. Intriguingly, recent reports have shown a significant association of loneliness with a higher amyloid- β (Aβ) burden, suggesting that SI is linked to the pathophysiology of AD. Numerous studies, using rodents or other animal models have revealed diverse biological effects of SI, including induction of oxidative stress and activation of neuroinflammation. Furthermore, using transgenic mouse models of AD, recent investigations have shown that SI affects AD pathology, particularly the deposition of Aβ and neuroinflammation. However, it remains unclarified, by which mechanisms SI confers a significant risk for AD. In this narrative mini-review, I overview published studies on the pathobiological effects of SI in rodent models and discuss the mechanisms by which SI exacerbates AD pathology. Clarification of this issue has significant implications for the design of strategies for preventing cognitive impairment and dementia in the elderly population.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by hyperphosphorylation of tau protein to form neurofibrillary tangles (NFTs) and amyloid β (Aβ) deposition to form senile plaques, and its specific regulatory mechanism remains incompletely understood. Neurotrophic factors (NTFs) play important roles in neuronal growth, differentiation, and survival, and are considered to have potential therapeutic effects in AD.

Objective: This study aimed to investigate the effects of NTFs on tau protein phosphorylation in AD and its underlying mechanisms.

Methods: A correlation analysis was conducted between neurotrophic factors and tau protein phosphorylation genes using bioinformatics analysis. The relationship between the candidate neurotrophic factor NRN1 and tau protein phosphorylation was validated in vivo. The effects of NRN1 on tau protein phosphorylation, neural process-related proteins, and apoptosis were explored in vitro. Subsequently, GO and KEGG pathway enrichment analyses and PPI network were utilized to identify potential functions and pathways, as well as pinpoint core regulatory factors. Finally, the mechanism by which NRN1 affects tau protein phosphorylation was explored through Western blot analysis.

Results: Bioinformatics analysis revealed a significant negative correlation between NRN1 and MAPT, a gene linked to tau protein phosphorylation. Western blot analysis indicated a decrease in NRN1 expression and an increase in p-tau levels in the hippocampus of AD mice. NRN1 significantly reduced the expression of p-tau in AD cell models and enhanced the expression of MAP2, a protein related to neural processes. Further, apoptosis analysis demonstrated that NRN1 significantly decreased the level of cleaved caspase-3 and elevated the Bcl-2/Bax ratio. Bioinformatics analysis and PPI network construction suggested PIGU and CASP3 to play pivotal roles in NRN1 regulation of tau protein phosphorylation.

Conclusion: NRN1 may mitigate tau protein phosphorylation and neuronal apoptosis by modulating the PIGU-CASP3 pathway in AD. This finding offers novel insights into NRN1 as a potential target for the treatment of AD.

Aims: This study aims to explore the potential association between nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in oligodendrocytes and Alzheimer's disease (AD), utilizing a combination of bioinformatics analysis and molecular biology experiments to validate this relationship.

Methods: Public datasets related to AD were systematically retrieved and downloaded from the Gene Expression Omnibus (GEO) database at the National Center for Biotechnology Information (NCBI). Subsequently, the SVA package was employed to merge the data and eliminate batch effects, allowing for the precise identification of differentially expressed genes (DEGs) between AD patients and healthy controls. Advanced machine learning techniques, including LASSO regression analysis, random forest algorithms, and support vector machines (SVM), were utilized to analyze further the DEGs associated with the NLRP3 inflammasome to determine the gene set most closely related to AD. The effectiveness and clinical value of the gene-based diagnostic model were comprehensively assessed through receiver operating characteristic (ROC) curve analysis, nomogram construction, and decision curve analysis (DCA). Immune infiltration analysis evaluated the extent of various immune cell infiltrations in the brain tissue of AD patients. Single-cell transcriptomics and in vitro experiments were conducted to verify the molecular expression of NLRP3 in oligodendrocytes within the AD model.

Results: A total of 11 significant DEGs were identified, with 4 genes showing downregulation and 7 genes exhibiting upregulation. All three algorithms-LASSO regression, random forest, and SVM-consistently identified PANX1, APP, P2RX7, MEFV, and NLRP3 as key genes closely associated with AD. ROC curve analysis, nomogram modeling, and DCA results demonstrated that the diagnostic model constructed based on these five genes exhibited high diagnostic accuracy and clinical applicability. Immune infiltration analysis revealed a significant correlation between key genes associated with AD and various immune cells, particularly CD8+ T cells, monocytes, activated NK cells, and neutrophils, suggesting that these cells may play important roles in the immunopathological process of AD. Single-cell transcriptomics indicated that the expression level of NLRP3 in oligodendrocytes was higher in the AD group compared to the control group (p < 0.05). Additionally, in vitro cell experiments using Reverse transcription quantitative PCR(RT-qPCR), immunofluorescence (IF), and Western blot (WB) analysis confirmed that the expression level of NLRP3 in oligodendrocytes was elevated in the AD model relative to the control group (p < 0.05).

Conclusion: This study corroborates the high expression of NLRP3 in AD and its close relationship with the disease through integrated bioinformatics analysis and molecular biology e

Introduction: Khat (Catha edulis (Vahl) Forssk. ex Endl.), a stimulant plant native to Africa and Asia, contains psychoactive compounds such as cathinone and cathine that affect the central nervous system. This study aims to investigate the potential neurotoxicological risks associated with these compounds, particularly focusing on their possible relationship with neurodegenerative disorders like Alzheimer's disease (AD). The primary objective was to evaluate the toxicity of khat's main compounds and examine their molecular interactions with Monoamine Oxidase A (MAO-A), an enzyme implicated in the pathology of AD.

Methods: The toxicological profiles of cathinone, cathine, amphetamine, and the AD medication Donepezil were assessed using the Protox-3 server, which predicted toxicity class, potential for liver damage, carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity. Molecular docking studies were conducted to analyse the binding interactions of these compounds with MAO-A (PDB ID: 2Z5X). Binding affinities and key interacting residues were identified. The steric effects of the ligands within the enzyme's binding site were quantified by calculating the buried volume (%VBur) using the centroid of centres method.

Results: Protox-3 classified cathine and amphetamine as Class 3 toxicants (moderate toxicity), while cathinone and Donepezil were assigned to Class 4 (lower toxicity). Cathinone also demonstrated a moderate probability (0.64) of carcinogenicity. Molecular docking revealed that khat compounds had an average binding affinity of -5.81 ± 0.27 kcal/mol, which was lower than that of amphetamine (-6.10 ± 0.27 kcal/mol) and Donepezil (-7.80 ± 0.38 kcal/mol). Buried volume analysis indicated that khat compounds and amphetamine were more deeply embedded in the MAO-A binding site, correlating with stronger binding affinity.

Discussion: The computational results suggest that khat compounds exhibit moderate neurotoxic potential and interact with MAO-A in a manner that could be relevant to AD pathology. Although the binding affinities are lower than those of Amphetamine and Donepezil, they point to possible molecular-level interactions significant for neurodegeneration. Steric hindrance, as quantified by %VBur, appeared to influence binding strength, highlighting the importance of molecular fit within the active site.

Conclusion: This study presents evidence of a potential molecular link between khat consumption and an increased risk of Alzheimer's disease. The findings underscore the necessity for further in vivo and epidemiological research, particularly in regions with high rates of khat use, to assess its long-term neurotoxic effects.

Introduction: The aim of this study was to assess the relationship between serum biomarkers of vascular dysfunction and neuropsychological performance in Alzheimer's disease (AD) patients.

Materials and methods: In this cross-sectional observational study, outpatients with AD who were referred to the Neuropsychiatry Clinic of the Eginition Hospital in Athens from January 2006 to December 2006 were consecutively enrolled. All the participants underwent a neuropsychological assessment. The serum concentrations of Apolipoprotein A1 (ApoA1), Vascular Cell Adhesion Molecule 1 (VCAM- 1), Intercellular Adhesion Molecule 1 (ICAM-1), Lipoprotein-A (LpA), and C-Reactive Protein (CR-P) were determined.

Results: Fifty-six AD patients were enrolled. ApoA1 was correlated with Mini Mental State Examination (MMSE) and AD Cooperative Study-Activities of Daily Living (ADCS-ADL). Combined biomarkers were correlated with MMSE, Neuropsychiatry Inventory, Clinical Dementia Rating Scale, and ADCS-ADL.

Discussion: Our study highlights the association between serum biomarkers of vascular dysfunction- specifically ApoA1, VCAM-1, ICAM-1, LpA, and CRP-and the cognitive and behavioral features of Alzheimer's Disease.

Conclusion: These findings suggest that assessing vascular biomarkers may offer valuable insights into the pathophysiological mechanisms underlying cognitive and behavioral decline in AD.

Introduction: Neuropsychiatric symptoms frequently occur in patients with Alzheimer´s disease (AD); apathy, depression, delusions, optical hallucinations, anxiety, and agitation often appear as first symptoms of AD, while auditory hallucinations have never been described as the first symptom. In this case report, we describe a case of a woman who had auditory hallucinations as the first symptom of AD.

Case presentation: An 85-year-old woman was admitted to our hospital suffering from imperative auditory hallucinations without subjective and minimal objective memory complaints. Further diagnostics with an MRI scan, neuropsychological tests, and an analysis of cerebral spinal fluid were accomplished. AD was confirmed during the hospital stay, suggesting auditory hallucinations as the first symptom of AD. She was temporarily treated with risperidone, which improved the hallucinations.

Conclusion: Auditory hallucinations in older age could be the first symptom of AD and even occur before cognitive decline.

Objective/background: Type 2 Diabetes Mellitus (T2D) and Alzheimer's disease (AD) are two diseases with a high prevalence today that share common pathophysiological mechanisms, suggesting a potential causal relationship between them. AD is also known as Type 3 Diabetes Mellitus (T3D). A complete understanding of this complex issue (T2D-AD) is necessary to develop fully effective and easily applicable therapies that do not yet exist. A critical update on the subject is presented, delving into the pathophysiological implications and defining new research for promoting new therapeutic interventions.

Methods: Revision and critical analysis of the described and observed cellular and molecular common pathogenic T2D-AD mechanisms in human and model studies.

Results: Both diseases exhibit common genetic, epigenetic, biochemical and physiological characteristics. Pathogenic mechanisms such as peripheral inflammation, mitochondrial dysfunction, oxidative stress, insulin resistance, hyperglycemia, formation of advanced glycation end products, neuroinflammation, neuroglial dysfunctions, and deposition of aberrant misfolded proteins are commonly displayed in dysmetabolic diseases and AD. The T2D, AD and T2D-AD pathogenic courses present several close key contacts (or identities). The clinical course of T2D has different incidence in the neurodegenerative course of AD (from its onset to its aggravation). There are theoretical, practical and interpretative problems in studies on human and experimental models, as well as in the clinical and pathological interpretation of T2D-AD dementia, which are of great importance in the development of knowledge of this subject and the therapeutic application of its results.

Conclusion: In recent years, there has been a great advance in the study of the relationships between T2D (and related dysmetabolic diseases) and AD. There is no doubt about their close relationship and/or the inclusion of AD as a metabolic disease (T3D). Joint therapies seem to be absolutely necessary. Key pathogenic processes (insulin resistance, genetic and epigenetic regulation, peripheral inflammation and neuroinflammation) must be investigated to develop new and effective therapies.