Alzheimer's Pathway Research Articles

NXP031 restores memory function by dual effects degrading Aβ accumulation and facilitating antioxidant pathway in Alzheimer's disease models

Alzheimer’s disease (AD) is a representative neurodegenerative disease that is characterized by the overaccumulation of amyloid beta (Aβ) proteins. Since AD is accompanied by excessive oxidative stress, which aggravates neurological pathologies, the use of antioxidants has been considered to prevent disease development. NXP031, a combination of vitamin C (VitC) and an optimized aptamer that binds to VitC and stabilizes the reactivity of VitC, was designed. This study aimed to evaluate the effects of NXP031 on AD pathology, including Aβ accumulation, Aβ-induced oxidative stress, neuronal damage, and neuroinflammation. When NXP031 was administered to 5xFAD transgenic mice, NXP031 exerted a strong inhibitory action on Aβ accumulation, superior to that of VitC, by inducing an increase in Aβ-degrading endopeptidase expression. NXP031 diminished lipid peroxidation levels, activated Nrf2-mediated antioxidant pathways, and suppressed overactivated neuroinflammation. An in vitro study using Neuro2a cells revealed that NXP031 protects the cells against oxidative stress by regulating the MAPK signaling pathway-mediated apoptosis. Additionally, the neuroprotective effects of NXP031 were confirmed in a dose-dependent manner when administered to intrahippocampal Aβ-injected mice, as NXP031 attenuated memory decline, neuronal apoptosis, synaptic degeneration, and excessive glial activation, and reduced NOX-2 expression in the hippocampus. Taken together, NXP031 reduced the Aβ burden by regulating Aβ-degeneration and attenuated memory impairment, neuronal death, synaptic degeneration, and neuroinflammation induced by Aβ toxicity. These results suggest the potential of NXP031 as a therapeutic agent for AD.

From Plaques to Pathways in Alzheimer's Disease: The Mitochondrial-Neurovascular-Metabolic Hypothesis.

Alzheimer's disease (AD) presents a public health challenge due to its progressive neurodegeneration, cognitive decline, and memory loss. The amyloid cascade hypothesis, which postulates that the accumulation of amyloid-beta (Aβ) peptides initiates a cascade leading to AD, has dominated research and therapeutic strategies. The failure of recent Aβ-targeted therapies to yield conclusive benefits necessitates further exploration of AD pathology. This review proposes the Mitochondrial-Neurovascular-Metabolic (MNM) hypothesis, which integrates mitochondrial dysfunction, impaired neurovascular regulation, and systemic metabolic disturbances as interrelated contributors to AD pathogenesis. Mitochondrial dysfunction, a hallmark of AD, leads to oxidative stress and bioenergetic failure. Concurrently, the breakdown of the blood-brain barrier (BBB) and impaired cerebral blood flow, which characterize neurovascular dysregulation, accelerate neurodegeneration. Metabolic disturbances such as glucose hypometabolism and insulin resistance further impair neuronal function and survival. This hypothesis highlights the interconnectedness of these pathways and suggests that therapeutic strategies targeting mitochondrial health, neurovascular integrity, and metabolic regulation may offer more effective interventions. The MNM hypothesis addresses these multifaceted aspects of AD, providing a comprehensive framework for understanding disease progression and developing novel therapeutic approaches. This approach paves the way for developing innovative therapeutic strategies that could significantly improve outcomes for millions affected worldwide.

The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression

Alzheimer’s disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease’s impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.

Human-mouse proteomics reveals the shared pathways in Alzheimer's disease and delayed protein turnover in the amyloidome.

Murine models of Alzheimer's disease (AD) are crucial for elucidating disease mechanisms but have limitations in fully representing AD molecular complexities. We comprehensively profiled age-dependent brain proteome and phosphoproteome ( n > 10,000 for both) across multiple mouse models of amyloidosis. We identified shared pathways by integrating with human metadata, and prioritized novel components by multi-omics analysis. Collectively, two commonly used models (5xFAD and APP-KI) replicate 30% of the human protein alterations; additional genetic incorporation of tau and splicing pathologies increases this similarity to 42%. We dissected the proteome-transcriptome inconsistency in AD and 5xFAD mouse brains, revealing that inconsistent proteins are enriched within amyloid plaque microenvironment (amyloidome). Determining the 5xFAD proteome turnover demonstrates that amyloid formation delays the degradation of amyloidome components, including Aβ-binding proteins and autophagy/lysosomal proteins. Our proteomic strategy defines shared AD pathways, identify potential new targets, and underscores that protein turnover contributes to proteome-transcriptome discrepancies during AD progression.

The role of PI3K signaling pathway in Alzheimer's disease.

Alzheimer's disease (AD) is a debilitating progressively neurodegenerative disease. The best-characterized hallmark of AD, which is marked by behavioral alterations and cognitive deficits, is the aggregation of deposition of amyloid-beta (Aβ) and hyper-phosphorylated microtubule-associated protein Tau. Despite decades of experimental progress, the control rate of AD remains poor, and more precise deciphering is needed for potential therapeutic targets and signaling pathways involved. In recent years, phosphoinositide 3-kinase (PI3K) and Akt have been recognized for their role in the neuroprotective effect of various agents, and glycogen synthase kinase 3 (GSK3), a downstream enzyme, is also crucial in the tau phosphorylation and Aβ deposition. An overview of the function of PI3K/Akt pathway in the pathophysiology of AD is provided in this review, along with a discussion of recent developments in the pharmaceuticals and herbal remedies that target the PI3K/Akt signaling pathway. In conclusion, despite the challenges and hurdles, cumulative findings of novel targets and agents in the PI3K/Akt signaling axis are expected to hold promise for advancing AD prevention and treatment.

Linking gut microbiota dysbiosis to molecular pathways in Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and synaptic dysfunction. Emerging evidence suggests a significant relationship between gut microbiota and brain health, mediated through the gut-brain axis. Alterations in gut microbiota composition may influence AD progression by affecting molecular pathways and miRNA interactions. MethodsWe retrieved and analyzed microarray data from 34 tissue samples of AD patients and controls (GEO accession number GSE110298). Differentially expressed genes (DEGs) with the GCS score package in R, considering a p-value < 0.05 and logFC<-1 and logFC>1 to isolate significant gene clusters. Enrichment analysis of signaling pathways and gene ontology was conducted using Enrichr, KEGG, Panther, DAVID, and shiny GO databases. Protein-protein interactions were visualized with Networkanalyst and CytoScape. Gut microbiota in 200 CE patients was analyzed using next-generation sequencing (NGS) data from gutMDisorder and GMrepo databases. miRNA interactions were evaluated using miEAA, Targetscan, MienTurnet, and miRnet databases. ResultsSignificant reductions in microbial taxa, including Clostridia (LDA score −4.878208), Firmicutes (LDA score −4.817032), and Faecalibacterium (LDA score −4.40714), were observed in AD patients. Pathway analysis highlighted the involvement of Axon guidance, ErbB, and MAPK signaling pathways in AD. Venn diagram analysis identified 619 intersecting genes in brain and gut tissues, emphasizing pathways such as Axon Guidance and Cell Cycle. miRNA analysis revealed important regulatory miRNAs, including hsa-let-7c, hsa-mir-125b-2, and hsa-mir-145, which target key transcription factors involved in AD pathology. ConclusionThe study demonstrates significant dysbiosis in the gut microbiota of AD patients and underscores the potential role of gut microbiota in AD progression through altered signaling pathways and miRNA interactions. These findings highlight the need for further research into microbiota-based interventions as potential therapeutic strategies for AD.

The KEAP1/PGAM5/AIFM1-Mediated oxeiptosis pathway in Alzheimer’s disease

BackgroundAlzheimer’s Disease (AD) is a neurodegenerative disease with mitochondrial dysfunction and oxidative stress. Oxeiptosis is a cell death pathway sensitive to reactive oxygen species (ROS). This study investigates the role of oxeiptosis pathway and mitochondrial damage in AD. MethodsAn AD model was developed in C57BL/6 mice by injecting Aβ1-42 oligomers into the brain. Cognitive function was tested using the Morris water maze. Exposure of HT22 mouse hippocampal neurons to H2O2 induces oxidative stress. Protein levels of KEAP1, PGAM5 and AIFM1 were analyzed by western blot, and mitochondrial damage was observed with electron microscopy. Cell survival rates were using the CCK8 assay and flow cytometry after knocking down KEAP1, PGAM5 and AIFM1. ResultsThe protein concentrations of KEAP1, PGAM5 and AIFM1 were found to be elevated in the hippocampal tissues of AD mice compared to control group, accompanied by mitochondrial damage in the hippocampal neurons of the AD group. Similarly, in the HT22 oxidative stress model, there was an increase in the protein levels of KEAP1, PGAM5 and AIFM1, along with observed mitochondrial damage. Following individual and combined knockdown of KEAP1, PGAM5 and AIFM1, cell survival rates under oxidative stress conditions were higher compared to H2O2 group, with no significant difference in cell survival rates among the knockdown groups. ConclusionThis research underscores the critical role of the KEAP1/PGAM5/AIFM1-mediated oxeiptosis pathway in neuronal cell death, offering insights into potential therapeutic targets for mitigating neurodegeneration in AD.

Diosmin ameliorates inflammation, apoptosis and activates PI3K/AKT pathway in Alzheimer's disease rats.

Alzheimer's disease (AD), a prevalent cognitive disorder among the elderly, is frequently linked to the abnormal accumulation of myloid-β (Aβ), which is mainly as a result of neuronal death and inflammation. Diosmin, a flavonoid, is considered a potential drug for the treatment of AD. Our study aimed to uncover the molecular mechanism of diosmin in AD therapy. Here, rats were randomly divided into three groups: control, Aβ25-35, and Aβ25-35 + diosmin groups. AD model rats were induced by Aβ25-35 intraventricular injection, meanwhile 50mg/kg diosmin was orally administered for 6-week intervention. Morris water maze test assessed learning and memory abilities. Hippocampal neuronal damage was determined by HE, Nissl, and TUNEL staining. These assays indicate that diosmin improves cognitive dysfunction and reduces hippocampal neuronal loss and apoptosis. Western blot showed that diosmin reduced Bax (1.21 ± 0.12) and cleaved caspase-3 (1.27 ± 0.12) expression, and increased Bcl-2 (0.70 ± 0.06), p-PI3K (0.71 ± 0.08), and p-AKT (0.96 ± 0.10) in the hippocampus. ELISA indicated diosmin reduces IL-1β, IL-6, and TNF-α levels, suggesting anti-inflammation effect. These results suggest that diosmin inhibits neuronal apoptosis and neuroinflammatory responses to improve cognitive dysfunction in AD rats, possibly related to upregulation of the PI3K/AKT pathway, providing a scientific basis for its use in AD treatment.

Early biomarkers in the presymptomatic phase of cognitive impairment: changes in the endocannabinoidome and serotonergic pathways in Alzheimer's-prone mice after mTBI

BackgroundDespite extensive studies on the neurobiological correlates of traumatic brain injury (TBI), little is known about its molecular determinants on long-term consequences, such as dementia and Alzheimer’s disease (AD).MethodsHere, we carried out behavioural studies and an extensive biomolecular analysis, including inflammatory cytokines, gene expression and the combination of LC-HRMS and MALDI-MS Imaging to elucidate the targeted metabolomics and lipidomics spatiotemporal alterations of brains from wild-type and APP-SWE mice, a genetic model of AD, at the presymptomatic stage, subjected to mild TBI.ResultsWe found that brain injury does not affect cognitive performance in APP-SWE mice. However, we detected an increase of key hallmarks of AD, including Aβ1-42 levels and BACE1 expression, in the cortices of traumatized transgenic mice. Moreover, significant changes in the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), occurred, including increased levels of the endocannabinoid 2-AG in APP-SWE mice in both the cortex and hippocampus, and N-acylserotonins, detected for the first time in the brain. The gene expression of enzymes for the biosynthesis and inactivation of eCBs and eCB-like mediators, and some of their main molecular targets, also underwent significant changes. We also identified the formation of heteromers between cannabinoid 1 (CB1) and serotonergic 2A (5HT2A) receptors, whose levels increased in the cortex of APP-SWE mTBI mice, possibly contributing to the exacerbated pathophysiology of AD induced by the trauma.ConclusionsMild TBI induces biochemical changes in AD genetically predisposed mice and the eCBome may play a role in the pathogenetic link between brain injury and neurodegenerative disorders also by interacting with the serotonergic system.

Association of Alzheimer's Disease With Peripheral Vestibular Disorder: A Case-Control Study.

Vestibular disorders can impact cognitive domains, including spatial orientation and memory, which are also affected in Alzheimer's disease. This study aimed to examine the association between Alzheimer's disease and a prior diagnosis of peripheral vestibular disorders in the elderly Taiwanese population. The case-control study sample was retrieved from Taiwan's Longitudinal Health Insurance Database 2010. We included 3138 cases with Alzheimer's disease and 9414 propensity-matched controls. We conducted multivariable logistic regression modeling to investigate the association between Alzheimer's disease and a prior diagnosis of peripheral vestibular disorders after accounting for sociodemographic characteristics and medical comorbidities including diabetes, coronary heart disease, hypertension, hyperlipidemia, and hearing loss. The results revealed a statistically significant difference in the prevalence of prior peripheral vestibular disorders between patients with Alzheimer's disease and controls; 20.6% among patients with Alzheimer's disease and 11.4% among controls (p < 0.001). Multivariable logistic regression analysis found that patients with Alzheimer's disease were twice as likely as controls to have had a prior diagnosis of peripheral vestibular disorders, adjusted odds ratio 2.040 (95% confidence interval: 1.829-2.274). The findings suggest the possibility of shared or related pathophysiological pathways in Alzheimer's disease and vestibular dysfunction disorders. 3 Laryngoscope, 134:4730-4735, 2024.

Histone deacetylase-3 regulates the expression of the amyloid precursor protein and its inhibition promotes neuroregenerative pathways in Alzheimer's disease models.

HDAC3 inhibition has been shown to improve memory and reduce amyloid-β (Aβ) in Alzheimer's disease (AD) models, but the underlying mechanisms are unclear. We investigated the molecular effects of HDAC3 inhibition on AD pathology, using invitro and exvivo models of AD, based on our finding that HDAC3 expression is increased in AD brains. For this purpose, N2a mouse neuroblastoma cells as well as organotypic brain cultures (OBCSs) of 5XFAD and wild-type mice were incubated with various concentrations of the HDAC3 selective inhibitor RGFP966 (0.1-10 μM) for 24 h. Treatment with RGFP966 or HDAC3 knockdown in N2a cells was associated with an increase on amyloid precursor protein (APP) and mRNA expressions, without alterations in Aβ42 secretion. Invitro chromatin immunoprecipitation analysis revealed enriched HDAC3 binding at APP promoter regions. The increase in APP expression was also detected in OBCSs from 5XFAD mice incubated with 1 μM RGFP966, without changes in Aβ. In addition, HDAC3 inhibition resulted in a reduction of activated Iba-1-positive microglia and astrocytes in 5XFAD slices, which was not observed in OBCSs from wild-type mice. mRNA sequencing analysis revealed that HDAC3 inhibition modulated neuronal regenerative pathways related to neurogenesis, differentiation, axonogenesis, and dendritic spine density in OBCSs. Our findings highlight the complexity and diversity of the effects of HDAC3 inhibition on AD models and suggest that HDAC3 may have multiple roles in the regulation of APP expression and processing, as well as in the modulation of neuroinflammatory and neuroprotective genes.

Altered white matter functional pathways in Alzheimer's disease.

Alzheimer's disease (AD) is associated with functional disruption in gray matter (GM) and structural damage to white matter (WM), but the relationship to functional signal in WM is unknown. We performed the functional connectivity (FC) and graph theory analysis to investigate abnormalities of WM and GM functional networks and corpus callosum among different stages of AD from a publicly available dataset. Compared to the controls, AD group showed significantly decreased FC between the deep WM functional network (WM-FN) and the splenium of corpus callosum, between the sensorimotor/occipital WM-FN and GM visual network, but increased FC between the deep WM-FN and the GM sensorimotor network. In the clinical groups, the global assortativity, modular interaction between occipital WM-FN and visual network, nodal betweenness centrality, degree centrality, and nodal clustering coefficient in WM- and GM-FNs were reduced. However, modular interaction between deep WM-FN and sensorimotor network, and participation coefficients of deep WM-FN and splenium of corpus callosum were increased. These findings revealed the abnormal integration of functional networks in different stages of AD from a novel WM-FNs perspective. The abnormalities of WM functional pathways connect downward to the corpus callosum and upward to the GM are correlated with AD.

Effect of thymol on oxidative stress and reelin signaling pathway in Alzheimer's disease model.

The purpose of this study was to investigate how thymol affects cognitive functions and the levels of MDA, GSH, Aβ1-42, ApoE, reelin, and LRP8 in an AD model induced in male Wistar albino rats with the application of D-galactose (D-gal) and aluminum chloride (AlCl3). In this work, 3-month-old male Wistar albino rats were used. Group 1 served as the Control, Group 2 received 0.5 mL/day saline + 0.5 mL/day sunflower oil, Group 3 was administered 200 mg/kg/day AlCl3 + 60 mg/kg/day D-gal, Group 4 received 30 mg/kg/day thymol, and Group 5 was administered 200 mg/kg/day AlCl3 + 60 mg/kg/day D-gal + 30 mg/kg/day thymol. At the end of the 10-week experimental period, behavioral and memory tests were performed. GSH and MDA levels were measured in the obtained serum and brain tissue samples, while Aβ1-42, ApoE, reelin, and LRP8 levels were measured in brain tissue samples. Statistical analyses were performed using ANOVA test in Graphpad Prism V8.3 program. A p-value <0.05 was considered significant in intergroup analyses. When the novel object recognition test (NORT) results were evaluated, the Alzheimer + thymol (ALZ+TYM) group showed a significant increase in the recognition index (RI) and discrimination index (DI) compared to the Alzheimer (ALZ) group at the 24th hour. Thymol reduced working memory errors (WME), reference memory errors (RME), and maze completion time at 48, 72, and 96 hours when evaluated in terms of spatial memory in rats with Alzheimer's disease. Furthermore, Aβ1-42 and ApoE levels were increased in the ALZ group compared to the control (C), while reelin and LRP8 levels were decreased in the ALZ group compared to the C group. The data we obtained suggest that thymol may play an effective role in cognitive processes against AD and have an anti-Alzheimer's disease effect.

“Back to Braak”: Role of Nucleus Reuniens and Subcortical Pathways in Alzheimer’s Disease Progression

BackgroundPatients with Alzheimer’s Disease (AD) exhibit structural alterations of the thalamus that correlate with clinical symptoms. However, given the anatomical complexity of this brain structure, it is still unclear whether atrophy affects specific thalamic nuclei and modulates the clinical progression from a prodromal stage, known as Mild Cognitive Impairment (MCI), to full-fledged AD.ObjectivesTo characterize the structural integrity of distinct thalamic nuclei across the AD spectrum, testing whether MCI patients who convert to AD (c-MCI) show a distinctive pattern of thalamic structural alterations compared to patients who remain stable (s-MCI).DesignInvestigating between-group differences in the volumetric features of distinct thalamic nuclei across the AD spectrum.SettingProdromal and clinical stages of AD.ParticipantsWe analyzed data from 84 healthy control subjects (HC), 58 individuals with MCI, and 102 AD patients. The dataset was obtained from the AD Neuroimaging Initiative (ADNI-3) database. The MCI group was further divided into two subgroups depending on whether patients remained stable (s-MCI, n=22) or progressed to AD (s-MCI, n=36) in the 48 months following the diagnosis.MeasurementsA multivariate analysis of variance (MANOVA) assessed group differences in the volumetric features of distinct thalamic nuclei obtained from magnetic resonance (MR) images. A stepwise discriminant function analysis identified which feature most effectively predicted the conversion to AD. The corresponding predictive performance was evaluated through a Receiver Operating Characteristic approach.ResultsAD and c-MCI patients showed generalized atrophy of thalamic nuclei compared to HC. In contrast, no significant structural differences were observed between s-MCI and HC subjects. Compared to s-MCI, c-MCI individuals displayed significant atrophy of the nucleus reuniens and a trend toward significant atrophy in the anteroventral and laterodorsal nuclei. The discriminant function analysis confirmed the nucleus reuniens as a significant predictor of AD conversion, with a sensitivity of 0.73 and a specificity of 0.69.ConclusionsIn line with the pathophysiological relevance of the nucleus reuniens proposed by seminal post-mortem studies on patients with AD, we confirm the pivotal role of this nucleus as a critical hub in the clinical progression to AD. We also propose a theoretical model to explain the evolving dysfunction of subcortical brain networks in the disease process.

Silencing Apoe with divalent-siRNAs improves amyloid burden and activates immune response pathways in Alzheimer's disease.

The most significant genetic risk factor for late-onset Alzheimer's disease (AD) is APOE4, with evidence for gain- and loss-of-function mechanisms. A clinical need remains for therapeutically relevant tools that potently modulate APOE expression. We optimized small interfering RNAs (di-siRNA, GalNAc) to potently silence brain or liver Apoe and evaluated the impact of each pool of Apoe on pathology. In adult 5xFAD mice, siRNAs targeting CNS Apoe efficiently silenced Apoe expression and reduced amyloid burden without affecting systemic cholesterol, confirming that potent silencing of brain Apoe is sufficient to slow disease progression. Mechanistically, silencing Apoe reduced APOE-rich amyloid cores and activated immune system responses. These results establish siRNA-based modulation of Apoe as a viable therapeutic approach, highlight immune activation as a key pathway affected by Apoe modulation, and provide the technology to further evaluate the impact of APOE silencing on neurodegeneration.

Unraveling the intercellular communication disruption and key pathways in Alzheimer's disease: an integrative study of single-nucleus transcriptomes and genetic association.

Recently, single-nucleus RNA-seq (snRNA-seq) analyses have revealed important cellular and functional features of Alzheimer's disease (AD), a prevalent neurodegenerative disease. However, our knowledge regarding intercellular communication mediated by dysregulated ligand-receptor (LR) interactions remains very limited in AD brains. We systematically assessed the intercellular communication networks by using a discovery snRNA-seq dataset comprising 69,499 nuclei from 48 human postmortem prefrontal cortex (PFC) samples. We replicated the findings using an independent snRNA-seq dataset of 56,440 nuclei from 18 PFC samples. By integrating genetic signals from AD genome-wide association studies (GWAS) summary statistics and whole genome sequencing (WGS) data, we prioritized AD-associated Gene Ontology (GO) terms containing dysregulated LR interactions. We further explored drug repurposing for the prioritized LR pairs using the Therapeutic Targets Database. We identified 190 dysregulated LR interactions across six major cell types in AD PFC, of which 107 pairs were replicated. Among the replicated LR signals, we found globally downregulated communications in the astrocytes-to-neurons signaling axis, characterized, for instance, by the downregulation of APOE-related and Calmodulin (CALM)-related LR interactions and their potential regulatory connections to target genes. Pathway analyses revealed 44 GO terms significantly linked to AD, highlighting Biological Processes such as 'amyloid precursor protein processing' and 'ion transmembrane transport,' among others. We prioritized several drug repurposing candidates, such as cromoglicate, targeting the identified dysregulated LR pairs. Our integrative analysis identified key dysregulated LR interactions in a cell type-specific manner and the associated GO terms in AD, offering novel insights into potential therapeutic targets involved in disrupted cell-cell communication in AD.

SARS‐CoV‐2 Associated Neurocognitive Disorder (SAND): Molecular validation of a pathogenetic hypothesis

AbstractBackgroundType I interferon signalling dysregulation is a hallmark of SARS‐CoV‐2 infection and among significantly perturbed pathways in Alzheimer’s disease. In a previous study, we predicted the involvement of this pathway in the development of SARS‐CoV‐2 Associated Neurocognitive Disorder (SAND) via a crosstalk between peripheral immunity and the CNS. The purpose of this study is to determine whether current data support provide external validation to our pathogenetic hypothesis.MethodData for our validation analyses were leveraged from studies of frontal cortex (FC) transcriptomes donated by Alzheimer’s disease and COVID‐19 patients vs. controls, respectively. An additional dataset of nasal epithelial cells from COVID‐19 patients was also used as a putative crosstalk site. Enrichment analyses were employed to provide an unbiased estimate of the enrichment of Type I interferon responses. Furthermore, we performed a literature search in order to identify studies on the effects of COVID‐19 on two different settings: (a) to determine the effects of peripheral exosome cargo on CNS tissue (b) to determine the cargo of neuronal‐derived exosomes. For enrichment analyses, a false discover rate (FDR) &lt;0.05 was considered statistically significant.ResultThe type I interferon pathway (IFN‐I; GO:0060337) was significantly enriched in both Alzheimer’s disease and COVID‐19 FC transcriptomes, as well as nasal epithelia of COVID‐19 patients. Common genes in both IFN‐I FC signatures included PSMB8, IP6K2, IFI35, EGR1, ISG20, MYD88, IFITM1, SP100, GBP2, IFITM3, OASL, IRF1, IRF2, MX2, IFNA2, IRF9, IFIT3, STAT2, HLA‐C, SAMHD1, IFI27, IFITM2, IRF7, BST2. At least one study reports on miR‐148a and miR‐590 as exosomal cargo of infected non‐neuronal cells capable of affecting IFN‐I responses and inducing microglial activation, supporting the role of exosomes as facilitators of IFN‐I crosstalk between the periphery and the CNS. Correspondingly, at least one study reports on proteopathic seeds as cargo of neuron‐derived exosomes.ConclusionIndependent studies and data support continue to corroborate our hypothesis that type I interferon pathway dysregulation as a result of peripheral – CNS immune crosstalk may mediate neuroinflammation and Alzheimer’s disease‐like pathology as observed in SAND.

Computational screening of foxtail millet (Setaria italica (L.) P.Beauv.) polyphenols for finding β-secretase (BACE 1) inhibitors that target the amyloidogenic pathway in Alzheimer's disease

Abstract BACKGROUND: Foxtail millet (FM; Setaria italica (L.) P.Beauv.) is known for its antioxidant and neuroprotective action against Alzheimer's disease (AD); hence the present study aims to screen its polyphenols to find less toxic and potentially effective anti-Alzheimer's drugs. MATERIALS AND METHODS: The details about phyto-compounds of FM and the β-secretase enzyme (BACE 1) of AD have been retrieved from the PubChem compound database and protein data bank, respectively. The Patch Dock server was used to carry out docking experiments. Initially, all the FM phytocompounds and reference drug (MK-8931) were subjected to docking, and subsequently, the best-docked complexes were selected based on their binding energy (in kcal/mol). Rule of five and adsorption, distribution, metabolism, excretion, and toxicity (ADMET) of selected compounds were analyzed using various computational tools. The final docking complexes were developed by using PyMOL. RESULTS: The molecular docking results revealed that among the 24 polyphenols studied, two compounds, namely N′-p-coumaroyl-N″-caffeoylspermidine (NPCNCS) and di-P-coumaroylspermidine (DPCS), demonstrated strong binding to the active site of β-secretase. and exhibited higher binding energies of -300.75 kcal/mol and -193.41 kcal/mol, respectively, in comparison to the reference drug MK-8931, with a binding energy of -154.36 kcal/mol. These compounds established hydrogen bond interactions with catalytic dyad (Asp 32 and Asp 228) and other accessory interactions with residues of the “flap” hairpin loop and “10s loop” of the β-secretase active site involved in the stabilization of substrate/inhibitor binding. In a nutshell, the NPCNCS and DPCS have shown more robust binding affinity than MK-8931 and docked well into the interior side of the active site. On the other hand, NPCNCS and DPCS have satisfied the RO5 and ADMET filters. CONCLUSIONS: The in silico analysis of FM polyphenols revealed that the N′-p-coumaroyl-N″-feruloylspermidine and di-P-coumaroylspermidine compounds exhibited non-toxic, permeability to blood-brain barrier and solid binding affinity toward β-secretase enzyme thereby; these millet compounds might be considered as β-secretase inhibitors for treating AD.

Synthetic and Natural Bioactive Molecules in Balancing the Crosstalk among Common Signaling Pathways in Alzheimer's Disease: Understanding the Neurotoxic Mechanisms for Therapeutic Intervention.

The structure and function of the brain greatly rely on different signaling pathways. The wide variety of biological processes, including neurogenesis, axonal remodeling, the development and maintenance of pre- and postsynaptic terminals, and excitatory synaptic transmission, depends on combined actions of these molecular pathways. From that point of view, it is important to investigate signaling pathways and their crosstalk in order to better understand the formation of toxic proteins during neurodegeneration. With recent discoveries, it is established that the modulation of several pathological events in Alzheimer's disease (AD) due to the mammalian target of rapamycin (mTOR), Wnt signaling, 5'-adenosine monophosphate activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), and sirtuin 1 (Sirt1, silent mating-type information regulator 2 homologue 1) are central to the key findings. These include decreased amyloid formation and inflammation, mitochondrial dynamics control, and enhanced neural stability. This review intends to emphasize the importance of these signaling pathways, which collectively determine the fate of neurons in AD in several ways. This review will also focus on the role of novel synthetic and natural bioactive molecules in balancing the intricate crosstalk among different pathways in order to prolong the longevity of AD patients.

An integrated neuroimaging-omics approach for the gut-brain communication pathways in Alzheimer's disease.

A key role of the gut microbiota in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), has been identified over the past decades. Increasing clinical and preclinical evidence implicates that there is bidirectional communication between the gut microbiota and the central nervous system (CNS), which is also known as the microbiota-gut-brain axis. Nevertheless, current knowledge on the interplay between gut microbiota and the brain remains largely unclear. One of the primary mediating factors by which the gut microbiota interacts with the host is peripheral metabolites, including blood or gut-derived metabolites. However, mechanistic knowledge about the effect of the microbiome and metabolome signaling on the brain is limited. Neuroimaging techniques, such as multi-modal magnetic resonance imaging (MRI), and fluorodeoxyglucose-positron emission tomography (FDG-PET), have the potential to directly elucidate brain structural and functional changes corresponding with alterations of the gut microbiota and peripheral metabolites in vivo. Employing a combination of gut microbiota, metabolome, and advanced neuroimaging techniques provides a future perspective in illustrating the microbiota-gut-brain pathway and further unveiling potential therapeutic targets for AD treatments.