Current Alzheimer Research - Online First

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.

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.

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.

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.

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.

Dementia is a set of acquired and progressive neuropsychiatric disorders. The most common types of dementia include Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD). Early intravital diagnosis of both types of dementia is difficult. Both molecular and neuroimaging markers are important for the diagnosis of different types of dementia.

This review employed freely accessible databases, including PubMed, Google Scholar, and ScienceDirect, using keywords such as molecular parameters, neuroimaging factors, dementia, FTD, Alzheimer’s disease, and fMRI.

Among the molecular markers of dementia, there are parameters common to its various types and enabling their differentiation. These parameters include both genetic and biochemical factors. Markers include genetic factors that help differentiate AD (APP, PSEN1, PSEN2) from FTD (e.g., TARDBP, FUS, MAPT). Simultaneously, there are important biochemical parameters differentiating AD (amyloid-beta (Aβ), neurofibrillary tangles) from FTD (TDP-43, FUS, and different forms of tau protein aggregates). Currently, there is growing interest in neuroimaging studies in the differential diagnosis of dementia. Positron Emission Tomography (PET) imaging enables the quantification and localization of Aβ deposits in the brain through the selective binding of the Pittsburgh Compound-B (PiB) ligand. This method has become the standard in AD diagnostics. In the context of magnetic resonance imaging studies, it is worth noting the search for structural differences between AD (mainly affecting the temporal lobe, including the hippocampus and entorhinal cortex, and the parietal lobe) and FTD (primarily involving the prefrontal cortex, anterior temporal lobes, and subcortical structures, as well as exhibiting an anteroposterior gradient of atrophy). However, the method of the future appears to be functional Magnetic Resonance Imaging (fMRI), especially since functional changes precede structural changes in the development of dementia.

The review encompasses the basic diagnostic criteria for AD and FTD dementia, as well as molecular and neuroimaging parameters important for the intravital diagnosis of these dementias. It seems that the use of fMRI can contribute to both early diagnosis and early introduction of targeted treatment in developing dementia. Although it is not yet widely used clinically, its diagnostic value is increasingly recognized.

The benefits of fMRI studies complementing molecular markers in the diagnosis of dementia were highlighted.

Nowadays, the large increase in environmental pollutants has led to the occurrence and development of an increasing number of diseases. Studies have shown that exposure to environmental pollutants, such as methyl-4-hydroxybenzoate (MEP) may lead to Alzheimer's disease (AD). Therefore, the purpose of this study was to elucidate the complex effects and potential molecular mechanisms of environmental pollutants MEP on AD.

Through exhaustive exploration of databases, such as ChEMBL, STITCH, SwissTargetPrediction, and Gene Expression Omnibus DataSets (GEO DataSets), we have identified a comprehensive list of 46 potential targets closely related to MEP and AD. After rigorous screening using the STRING platform and Cytoscape software, we narrowed the list to nine candidate targets and ultimately identified six hub targets using three proven machine learning methods (LASSO, RF, and SVM): CREBBP, BCL6, CXCR4, GRIN1, GOT2, and ITGA5. The “clusterProfiler” R package was used to conduct GO and KEGG enrichment analysis. At the same time, we also constructed disease prediction models for core genes. At last, six hub targets were executed molecular docking.

We derived 46 key target genes related to MEP and AD and conducted gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. MEP might play a role in AD by affecting the pathways of neuroactive ligand-receptor interaction. Nine genes were screened as pivotal targets, followed by machine learning methods to identify six hub targets. Molecular docking analysis showed a good binding ability between MEP and CREBBP, BCL6, CXCR4, GRIN1, GOT2 and ITGA5. In addition, changes in the immune microenvironment revealed a significant impact of immune status on AD.

This study revealed that MEP may induce AD through multiple mechanisms, such as oxidative stress, neurotoxicity, and immune regulation, and identified six core targets (CREBBP, BCL6, etc.) and found that they are related to changes in the immune microenvironment, such as T cells and B cells, providing new molecular targets for AD intervention.

Overall, CREBBP, BCL6, CXCR4, GRIN1, GOT2, and ITGA5 have been identified as the crucial targets correlating with AD. Our findings provide a theoretical framework for understanding the complex molecular mechanisms underlying the effects of MEP on AD and provide insights for the development of prevention and treatment of AD caused by exposure to MEP.

Currently, there is no information on changes in the mitophagy (BNIP3), apoptosis (CASP3), and autophagy (BECN1) genes in the frontal cortex after brain ischemia with animal survival for 2 years. Furthermore, it is not known whether the BNIP3, CASP3, and BECN1 genes possess any influence on neurons in the frontal cortex due to ischemia.

The goal of the investigation was to evaluate alterations in the behavior of BNIP3, CASP3, and BECN1 genes in the frontal cortex following ischemia with survival of 2 years.

Gene expression was assessed using an RT-PCR protocol at 2-30 days and 6-24-months after ischemia.

BECN1 gene expression after ischemic injury was lower than the control group during 7-30- days and 18 months, whereas overexpression was noted after 2 days, 6-, 12- and 24 months. In the case of BNIP3 gene expression, it was lower than the control group for 2-7 days and higher than the control throughout the remaining time after ischemia. Increased expression of the CASP3 gene was observed except on days 7-30 following ischemia when its expression was lower compared to control values.

The data seem to indicate that the observed changes in gene expression may reflect the activation and inhibition of different mechanisms involved in the advancement of neurodegeneration after ischemia.

Overexpression of BECN1gene is likely to be associated with the induction of neuroprotective phenomena, whereas overexpression of BNIP3 and CASP3 genes can cause harmful effects.

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.

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.

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.

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.

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

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.

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.

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).

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.

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.

Alzheimer’s disease is associated with dysfunction of the cholinergic system, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) a promising therapeutic approach.

This study aimed to evaluate the neuroprotective effects and toxicity of essential oil (EO) and carlina oxide from Carthamus caeruleus in mice, assessing their potential for Alzheimer’s disease treatment.

The chemical composition of the essential oil extracted from the roots of Carthamus caeruleus was analyzed using gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The main component, carlina oxide, was isolated via column chromatography. The inhibitory activities of AChE and BChE were evaluated in vitro for both the essential oil and carlina oxide. Additionally, in vivo, toxicity was assessed in laboratory mice.

Chemical analysis identified carlina oxide (81.6%) as the major constituent, along with minor compounds such as 13-methoxycarlin oxide and hexadecanoic acid. Both the essential oil and its main component, carlina oxide, exhibited significant inhibitory activity against AChE and BChE, enzymes associated with Alzheimer’s disease. The essential oil demonstrated promising IC50 values, with stronger anti-BChE activity compared to the reference drug, galantamine. Toxicity tests in mice revealed no adverse effects at lower doses (0.2-0.5 g/kg). However, higher doses (1.0-2.0 g/kg) resulted in mild to significant toxicity, including weight loss and mortality.

The essential oil and carlina oxide demonstrated potent BChE inhibition, particularly relevant in advanced Alzheimer's disease. While effective at low doses, signs of toxicity were observed at higher concentrations, highlighting the importance of dose optimization. These findings suggest that C. caeruleus may serve as a natural source of cholinesterase inhibitors, pending further in vivo studies and clinical validation.

Carthamus caeruleus essential oil and carlina oxide show promising inhibitory effects on AChE and BChE, suggesting their potential as neuroprotective agents. However, their toxicity at higher doses highlights the need for cautious use and further investigation.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting the central nervous system (CNS), with its etiology still shrouded in uncertainty. The interplay of extracellular amyloid-β (Aβ) deposition, intracellular neurofibrillary tangles (NFTs) composed of tau protein, cholinergic neuronal impairment, and other pathogenic factors is implicated in the progression of AD.

The current study endeavors to delineate the proteomic landscape alterations in the hippocampus of an AD murine model, utilizing proteomic analysis to identify key physiological and pathological shifts induced by the disease. This endeavor aims to shed light on the underlying pathogenic mechanisms, which could facilitate early diagnosis and pave the way for novel therapeutic interventions for AD.

To dissect the proteomic perturbations induced by Aβ and Presenilin-1 (PS1) in the AD pathogenesis, we undertook a label-free quantitative (LFQ) proteomic analysis focusing on the hippocampal proteome of the APP/PS1 transgenic mouse model. Employing a multi-faceted approach that included differential protein functional enrichment, cluster analysis, and protein-protein interaction (PPI) network analysis, we conducted a comprehensive comparative proteomic study between APP/PS1 transgenic mice and their wild-type C57BL/6 counterparts.

Mass spectrometry identified a total of 4817 proteins in the samples, with 2762 proteins being quantifiable. Comparative analysis revealed 396 proteins with differential expression between the APP/PS1 and control groups. Notably, 35 proteins exhibited consistent temporal regulation trends in the hippocampus, with concomitant alterations in biological pathways and PPI networks.

This study presents a comparative proteomic profile of transgenic (APP/PS1) and wild-type mice, highlighting the proteomic divergences. Furthermore, it charts the trajectory of proteomic changes in the AD mouse model across the developmental stages from 2 to 12 months, providing insights into the physiological and pathological implications of the disease-associated genetic mutations.