RESUMO
Alzheimer's disease (AD) is a debilitating neurodegenerative disorder with a global impact, yet its pathogenesis remains poorly understood. While age, metabolic abnormalities, and accumulation of neurotoxic substances are potential risk factors for AD, their effects are confounded by other factors. To address this challenge, we first utilized multi-omics data from 87 well phenotyped AD patients and generated plasma proteomics and metabolomics data, as well as gut and saliva metagenomics data to investigate the molecular-level alterations accounting the host-microbiome interactions. Second, we analyzed individual omics data and identified the key parameters involved in the severity of the dementia in AD patients. Next, we employed Artificial Intelligence (AI) based models to predict AD severity based on the significantly altered features identified in each omics analysis. Based on our integrative analysis, we found the clinical relevance of plasma proteins, including SKAP1 and NEFL, plasma metabolites including homovanillate and glutamate, and Paraprevotella clara in gut microbiome in predicting the AD severity. Finally, we validated the predictive power of our AI based models by generating additional multi-omics data from the same group of AD patients by following up for 3 months. Hence, we observed that these results may have important implications for the development of potential diagnostic and therapeutic approaches for AD patients.
Assuntos
Doença de Alzheimer , Microbioma Gastrointestinal , Metabolômica , Proteômica , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/microbiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/sangue , Feminino , Masculino , Idoso , Metabolômica/métodos , Índice de Gravidade de Doença , Inteligência Artificial , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Metagenômica/métodos , MultiômicaRESUMO
Neurodegenerative diseases such as Alzheimer's disease (AD) pose substantial challenges to patients and health-care systems, particularly in countries with aging populations. Immunotherapies, including the marketed antibodies lecanemab (Leqembi®) and donanemab (KisunlaTM), offer promise but face hurdles due to limited delivery across the blood-brain barrier (BBB). This limitation necessitates high doses, resulting in increased costs and a higher risk of side effects. This study explores transferrin receptor (TfR)-binding camelid single-domain antibodies (VHHs) for facilitated brain delivery. We developed and evaluated fusion proteins (FPs) combining VHHs with human IgG Fc domains or single-chain variable fragments (scFvs) of the anti-amyloid-beta (Aß) antibody 3D6. In vitro assessments showed varying affinities of the FPs for TfR. In vivo evaluations indicated that specific VHH-Fc and VHH-scFv fusions reached significant brain concentrations, emphasizing the importance of optimal TfR binding affinities. The VHH-scFv fusions were further investigated in mouse models with Aß pathology, showing higher retention compared to wild-type mice without Aß pathology. Our findings suggest that these novel VHH-based FPs hold potential for therapeutic and diagnostic applications in AD, providing a strategy to overcome BBB limitations and enhance brain targeting of antibody-based treatments. Furthermore, our results suggest that a given bispecific TfR-binding fusion format has a window of "optimal" affinity where parenchymal delivery is adequate, while blood pharmacokinetics aligns with the desired application of the fusion protein.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Barreira Hematoencefálica , Receptores da Transferrina , Anticorpos de Cadeia Única , Anticorpos de Domínio Único , Barreira Hematoencefálica/metabolismo , Animais , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Receptores da Transferrina/imunologia , Receptores da Transferrina/metabolismo , Anticorpos de Cadeia Única/imunologia , Humanos , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Anticorpos de Domínio Único/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Encéfalo/metabolismo , Encéfalo/imunologia , Imunoconjugados/imunologia , Imunoconjugados/farmacologia , Imunoconjugados/farmacocinéticaRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques and cognitive decline, the latter of which is thought to be driven by soluble oligomeric amyloid-ß (oAß). The dysregulation of G protein-gated inwardly rectifying K+ (GIRK; also known as Kir3) channels has been implicated in rodent models of AD. Here, seeking mechanistic insights, we uncovered a sex-dependent facet of GIRK-dependent signaling in AD-related amyloid pathophysiology. Synthetic oAß1-42 suppressed GIRK-dependent signaling in hippocampal neurons from male mice, but not from female mice. This effect required cellular prion protein, the receptor mGluR5, and production of arachidonic acid by the phospholipase PLA2. Although oAß suppressed GIRK channel activity only in male hippocampal neurons, intrahippocampal infusion of oAß or genetic suppression of GIRK channel activity in hippocampal pyramidal neurons impaired performance on a memory test in both male and female mice. Moreover, genetic enhancement of GIRK channel activity in hippocampal pyramidal neurons blocked oAß-induced cognitive impairment in both male and female mice. In APP/PS1 AD model mice, GIRK-dependent signaling was diminished in hippocampal CA1 pyramidal neurons from only male mice before cognitive deficit was detected. However, enhancing GIRK channel activity rescued cognitive deficits in older APP/PS1 mice of both sexes. Thus, whereas diminished GIRK channel activity contributes to cognitive deficits in male mice with increased oAß burden, enhancing its activity may have therapeutic potential for both sexes.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G , Hipocampo , Animais , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Peptídeos beta-Amiloides/metabolismo , Feminino , Masculino , Hipocampo/metabolismo , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Neurônios/metabolismo , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptor de Glutamato Metabotrópico 5/genética , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/genética , Caracteres Sexuais , Modelos Animais de Doenças , Fosfolipases A2/metabolismo , HumanosRESUMO
Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.
Assuntos
Doença de Alzheimer , Microscopia Crioeletrônica , Tomografia por Emissão de Pósitrons , Proteínas tau , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Proteínas tau/metabolismo , Proteínas tau/química , Proteínas tau/ultraestrutura , Tomografia por Emissão de Pósitrons/métodos , Humanos , Microscopia Crioeletrônica/métodos , Ligantes , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Autorradiografia , Feminino , Masculino , CarbolinasRESUMO
Recent advancements in Alzheimer's disease (AD) research have led to the approval of lecanemab and donanemab, highlighting the effectiveness of amyloid-beta (Aß) degradation as a treatment for AD. The prospect of small molecule Aß degraders as a potential treatment, which utilizes emerging targeted protein degradation technology, is exciting, given their ability to address some of the limitations of current therapies and their promising future in AD treatment. Despite facing challenges, these degraders are poised to become a future treatment option, harnessing scientific breakthroughs for more targeted and effective AD therapy.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Proteólise , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Humanos , Proteólise/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Desenvolvimento de Medicamentos/métodosRESUMO
Alzheimer's disease is associated with the misfolding and aggregation of two distinct proteins, beta-amyloid and tau. Previously, it has been shown that activation of the cytoprotective heat shock response (HSR) pathway reduces beta-amyloid toxicity. Here, we show that activation of the HSR is also protective against tau toxicity in a cell-autonomous manner. Overexpression of HSF-1, the master regulator of the HSR, ameliorates the motility defect and increases the lifespan of transgenic C. elegans expressing human tau. By contrast, RNA interference of HSF-1 exacerbates the motility defect and shortens lifespan. Targeting regulators of the HSR also affects tau toxicity. Additionally, two small-molecule activators of the HSR, Geranylgeranylacetone (GGA) and Arimoclomol (AC), have substantial beneficial effects. Taken together, this research expands the therapeutic potential of HSR manipulation to tauopathies and reveals that the HSR can impact both beta-amyloid and tau proteotoxicity in Alzheimer's disease.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Diterpenos , Resposta ao Choque Térmico , Proteínas tau , Proteínas tau/metabolismo , Resposta ao Choque Térmico/efeitos dos fármacos , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Humanos , Diterpenos/farmacologia , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Animais Geneticamente Modificados , Longevidade/efeitos dos fármacos , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Fatores de TranscriçãoRESUMO
Diabetes mellitus (DM) and Alzheimer's disease (AD) rates are rising, mirroring the global trend of an aging population. Numerous epidemiological studies have shown that those with Type 2 diabetes (T2DM) have an increased risk of developing dementia. These degenerative and progressive diseases share some risk factors. To a large extent, the amyloid cascade is responsible for AD development. Neurofibrillary tangles induce neurodegeneration and brain atrophy; this chain reaction begins with hyperphosphorylation of tau proteins caused by progressive amyloid beta (Aß) accumulation. In addition to these processes, it seems that alterations in brain glucose metabolism and insulin signalling lead to cell death and reduced synaptic plasticity in AD, before the onset of symptoms, which may be years away. Due to the substantial evidence linking insulin resistance in the brain with AD, researchers have coined the name "Type 3 diabetes" to characterize the condition. We still know little about the processes involved, even though current animal models have helped illuminate the links between T2DM and AD. This brief overview discusses insulin and IGF-1 signalling disorders and the primary molecular pathways that may connect them. The presence of GSK-3ß in AD is intriguing. These proteins' association with T2DM and pancreatic ß-cell failure suggests they might be therapeutic targets for both disorders.
Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Animais , Transdução de Sinais , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismoRESUMO
Cortisol dysregulation, neuroinflammation, and cerebrovascular dysfunction are biological processes that have been separately shown to be affected in Alzheimer's disease (AD). Here, we aimed to identify biomarker signatures reflecting these pathways in 108 memory clinic patients with subjective cognitive decline (SCD, N = 40), mild cognitive impairment (MCI, N = 39), and AD (N = 29). Participants were from the well-characterized Cortisol and Stress in Alzheimer's Disease (Co-STAR) cohort, recruited at Karolinska University Hospital. Salivary diurnal cortisol measures and 41 CSF proteins were analyzed. Principal component analysis was applied to identify combined biosignatures related to AD pathology, synaptic loss, and neuropsychological assessments, in linear regressions adjusted for confounders, such as age, sex, education and diagnosis. We found increased CSF levels of C-reactive protein (CRP), interferon γ-inducible protein (IP-10), thymus and activation-regulated chemokine (TARC), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in MCI patients. Further, markers of cortisol dysregulation (flattened salivary cortisol awakening response and flattened cortisol slope) correlated with increased levels of placental growth factor (PlGF), IP-10, and chitinase 3-like 1 (YKL-40) in the total cohort. A biosignature composed of cortisol awakening response, cortisol slope, and CSF IL-6 was downregulated in AD patients. Moreover, biomarker signatures reflecting overlapping pathophysiological processes of neuroinflammation and vascular injury were associated with AD pathology, synaptic loss, and worsened processing speed. Our findings suggest an early dysregulation of immune and cerebrovascular processes during the MCI stage and provide insights into the interrelationship of chronic stress and neuroinflammation in AD.
Assuntos
Doença de Alzheimer , Biomarcadores , Transtornos Cerebrovasculares , Disfunção Cognitiva , Hidrocortisona , Saliva , Humanos , Feminino , Masculino , Hidrocortisona/metabolismo , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Idoso , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/líquido cefalorraquidiano , Pessoa de Meia-Idade , Saliva/química , Saliva/metabolismo , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/líquido cefalorraquidiano , Estudos de Coortes , Ritmo Circadiano/fisiologia , Doenças Neuroinflamatórias/líquido cefalorraquidiano , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Testes Neuropsicológicos , Quimiocina CXCL10/líquido cefalorraquidiano , Quimiocina CXCL10/metabolismoRESUMO
Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer's disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10-8) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson's disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Paralisia Supranuclear Progressiva , Proteínas tau , Humanos , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/patologia , Paralisia Supranuclear Progressiva/metabolismo , Idoso , Masculino , Feminino , Proteínas tau/genética , Proteínas tau/metabolismo , Transcriptoma , Polimorfismo de Nucleotídeo Único , Neuroglia/metabolismo , Neuroglia/patologia , Idoso de 80 Anos ou mais , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Pessoa de Meia-Idade , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Estudos de Casos e Controles , Proteínas da MielinaRESUMO
Age-related neurodegenerative disorders like Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by deposits of protein aggregates, or amyloid, in various regions of the brain. Historically, aggregation of a single protein was observed to be correlated with these different pathologies: tau in AD and α-synuclein (αS) in PD. However, there is increasing evidence that the pathologies of these two diseases overlap, and the individual proteins may even promote each other's aggregation. Both tau and αS are intrinsically disordered proteins (IDPs), lacking stable secondary and tertiary structure under physiological conditions. In this study we used a combination of biochemical and biophysical techniques to interrogate the interaction of tau with both soluble and fibrillar αS. Fluorescence correlation spectroscopy (FCS) was used to assess the interactions of specific domains of fluorescently labeled tau with full length and C-terminally truncated αS in both monomer and fibrillar forms. We found that full-length tau as well as individual tau domains interact with monomer αS weakly, but this interaction is much more pronounced with αS aggregates. αS aggregates also mildly slow the rate of tau aggregation, although not the final degree of aggregation. Our findings suggest that co-occurrence of tau and αS in disease are more likely to occur through monomer-fiber binding interactions, rather than monomer-monomer or co-aggregation.
Assuntos
alfa-Sinucleína , Proteínas tau , alfa-Sinucleína/metabolismo , alfa-Sinucleína/química , Proteínas tau/metabolismo , Proteínas tau/química , Humanos , Ligação Proteica , Agregados Proteicos , Amiloide/metabolismo , Amiloide/química , Espectrometria de Fluorescência , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Agregação Patológica de Proteínas/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologiaRESUMO
Periodontitis is a common chronic inflammatory disease, affecting approximately 19% of the global adult population. A relationship between periodontal disease and Alzheimer disease has long been recognized, and recent evidence has been uncovered to link these 2 diseases mechanistically. Periodontitis is caused by dysbiosis in the subgingival plaque microbiome, with a pronounced shift in the oral microbiota from one consisting primarily of Gram-positive aerobic bacteria to one predominated by Gram-negative anaerobes, such as Porphyromonas gingivalis. A common phenomenon shared by all bacteria is the release of membrane vesicles to facilitate biomolecule delivery across long distances. In particular, the vesicles released by P gingivalis and other oral pathogens have been found to transport bacterial components across the blood-brain barrier, initiating the physiologic changes involved in Alzheimer disease. In this review, we summarize recent data that support the relationship between vesicles secreted by periodontal pathogens to Alzheimer disease pathology.
Assuntos
Doença de Alzheimer , Periodontite , Porphyromonas gingivalis , Doença de Alzheimer/microbiologia , Doença de Alzheimer/metabolismo , Humanos , Periodontite/microbiologia , Porphyromonas gingivalis/patogenicidade , Disbiose/microbiologia , Infecções Bacterianas/microbiologia , Barreira Hematoencefálica/microbiologia , Animais , MicrobiotaRESUMO
BACKGROUND: Emerging evidence suggests that viral infections may contribute to Alzheimer's disease (AD) onset and/or progression. However, the extent of their involvement and the mechanisms through which specific viruses increase AD susceptibility risk remain elusive. METHODS: We used an integrative systems bioinformatics approach to identify viral-mediated pathogenic mechanisms, by which Herpes Simplex Virus 1 (HSV-1), Human Cytomegalovirus (HCMV), Epstein-Barr virus (EBV), Kaposi Sarcoma-associated Herpesvirus (KSHV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Influenza A Virus (IAV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) could facilitate AD pathogenesis via virus-host protein-protein interactions (PPIs). We also explored potential synergistic pathogenic effects resulting from herpesvirus reactivation (HSV-1, HCMV, and EBV) during acute SARS-CoV-2 infection, potentially increasing AD susceptibility. RESULTS: Herpesviridae members (HSV-1, EBV, KSHV, HCMV) impact AD-related processes like amyloid-ß (Aß) formation, neuronal death, and autophagy. Hepatitis viruses (HBV, HCV) influence processes crucial for cellular homeostasis and dysfunction, they also affect microglia activation via virus-host PPIs. Reactivation of HCMV during SARS-CoV-2 infection could potentially foster a lethal interplay of neurodegeneration, via synergistic pathogenic effects on AD-related processes like response to unfolded protein, regulation of autophagy, response to oxidative stress, and Aß formation. CONCLUSIONS: These findings underscore the complex link between viral infections and AD development. Viruses impact AD-related processes through shared and distinct mechanisms, potentially influencing variations in AD susceptibility.
Assuntos
Doença de Alzheimer , Biologia Computacional , SARS-CoV-2 , Viroses , Humanos , Doença de Alzheimer/virologia , Doença de Alzheimer/metabolismo , Biologia Computacional/métodos , Viroses/virologia , SARS-CoV-2/fisiologia , COVID-19/virologia , Herpesviridae/genética , Herpesviridae/fisiologiaRESUMO
BACKGROUND: Toxoplasma gondii infection of Alzheimer's disease model mice decreases amyloid ß plaques. We aimed to determine if there is a brain regional difference in amyloid ß reduction in the brains of T. gondii-infected compared to control mice. METHOD: Three-month-old 5xFAD (AD model) mice were injected with T. gondii or with phosphate-buffered saline as a control. Intact brains were harvested at 6 weeks postinfection, optically cleared using iDISCO+, and brain-wide amyloid burden was visualized using volumetric light-sheet imaging. Amyloid signal was quantified across each brain and computationally mapped to the Allen Institute Brain Reference Atlas to determine amyloid density in each region. RESULTS: A brain-wide analysis of amyloid in control and T. gondii-infected 5xFAD mice revealed that T. gondii infection decreased amyloid burden in the brain globally as well as in the cortex and hippocampus, and many daughter regions. Daughter regions that showed reduced amyloid burden included the prelimbic cortex, visual cortex, and retrosplenial cortex. The olfactory tubercle, a region known to have increased monocytes following T. gondii infection, also showed reduced amyloid after infection. CONCLUSIONS: T. gondii infection of AD mice reduces amyloid burden in a brain region-specific manner that overlaps with known regions of T. gondii infection and peripheral immune cell infiltration.
Assuntos
Doença de Alzheimer , Encéfalo , Modelos Animais de Doenças , Camundongos Transgênicos , Toxoplasma , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/parasitologia , Doença de Alzheimer/patologia , Camundongos , Encéfalo/parasitologia , Encéfalo/metabolismo , Encéfalo/patologia , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Toxoplasmose/metabolismo , FemininoRESUMO
Alzheimer's disease (AD) is a significant global healthcare challenge, particularly in the elderly population. This neurodegenerative disorder is characterized by impaired memory and progressive decline in cognitive function. BACE1, a transmembrane protein found in neurons, oligodendrocytes, and astrocytes, exhibits varying levels across different neural subtypes. Abnormal BACE1 activity in the brains of individuals with AD leads to the formation of beta-amyloid proteins. The complex interplay between myelin sheath formation, BACE1 activity, and beta-amyloid accumulation suggests a critical role in understanding the pathological mechanisms of AD. The primary objective of this study was to identify molecular inhibitors that target Aß. Structure-based virtual screening (SBVS) was employed using the MCULE database, which houses over 2 million chemical compounds. A total of 59 molecules were selected after the toxicity profiling. Subsequently, five compounds conforming to the Egan-Egg permeation predictive model of the ADME rules were selected and subjected to molecular docking using AutoDock Vina on the Mcule drug discovery platform. The top two ligands and the positive control, 5HA, were subjected to molecular dynamics simulation for five nanoseconds. Toxicity profiling, physiochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, average potential energy, RMSD, RMSF, and Rg analyses were conducted to identify the ligand MCULE-9199128437-0-2 as a promising inhibitor of BACE1.
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Secretases da Proteína Precursora do Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/química , Humanos , Ligantes , Descoberta de Drogas/métodos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/químicaRESUMO
Alzheimer's disease (AD) is the most common cause of dementia, characterized by memory loss, cognitive decline, personality changes, and various neurological symptoms. The role of blood-brain barrier (BBB) injury, extracellular matrix (ECM) abnormalities, and oligodendrocytes (ODCs) dysfunction in AD has gained increasing attention, yet the detailed pathogenesis remains elusive. This study integrates single-cell sequencing of AD patients' cerebrovascular system with a genome-wide association analysis. It aims to elucidate the associations and potential mechanisms behind pericytes injury, ECM disorder, and ODCs dysfunction in AD pathogenesis. Finally, we identified that abnormalities in the pericyte PI3K-AKT-FOXO signaling pathway may be involved in the pathogenic process of AD. This comprehensive approach sheds new light on the complex etiology of AD and opens avenues for advanced research into its pathogenesis and therapeutic strategies.
Assuntos
Doença de Alzheimer , Barreira Hematoencefálica , Estudo de Associação Genômica Ampla , Pericitos , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/etiologia , Humanos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Pericitos/patologia , Pericitos/metabolismo , Transdução de Sinais , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Matriz Extracelular/metabolismo , Microvasos/patologia , Microvasos/metabolismo , Análise de Célula Única , Feminino , Masculino , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
Sleep and circadian rhythm dysfunctions are common clinical features of Alzheimer's disease (AD). Increasing evidence suggests that in addition to being a symptom, sleep disturbances can also drive the progression of neurodegeneration. Protein aggregation is a pathological hallmark of AD; however, the molecular pathways behind how sleep affects protein homeostasis remain elusive. Here we demonstrate that sleep modulation influences proteostasis and the progression of neurodegeneration in Drosophila models of tauopathy. We show that sleep deprivation enhanced Tau aggregational toxicity resulting in exacerbated synaptic degeneration. In contrast, sleep induction using gaboxadol led to reduced toxic Tau accumulation in neurons as a result of modulated autophagic flux and enhanced clearance of ubiquitinated Tau, suggesting altered protein processing and clearance that resulted in improved synaptic integrity and function. These findings highlight the complex relationship between sleep and regulation of protein homeostasis and the neuroprotective potential of sleep-enhancing therapeutics to slow the progression or delay the onset of neurodegeneration.
Assuntos
Doença de Alzheimer , Autofagia , Modelos Animais de Doenças , Proteostase , Sono , Proteínas tau , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Sono/fisiologia , Proteínas tau/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Neurônios/metabolismo , Drosophila melanogaster/metabolismo , Humanos , Drosophila , Privação do Sono/metabolismo , Privação do Sono/fisiopatologia , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/etiologiaRESUMO
Recent advances in high-throughput measurement technologies have enabled the analysis of molecular perturbations associated with disease phenotypes at the multi-omic level. Such perturbations can range in scale from fluctuations of individual molecules to entire biological pathways. Data-driven clustering algorithms have long been used to group interactions into interpretable functional modules; however, these modules are typically constrained to a fixed size or statistical cutoff. Furthermore, modules are often analyzed independently of their broader biological context. Consequently, such clustering approaches limit the ability to explore functional module associations with disease phenotypes across multiple scales. Here, we introduce AutoFocus, a data-driven method that hierarchically organizes biomolecules and tests for phenotype enrichment at every level within the hierarchy. As a result, the method allows disease-associated modules to emerge at any scale. We evaluated this approach using two datasets: First, we explored associations of biomolecules from the multi-omic QMDiab dataset (n = 388) with the well-characterized type 2 diabetes phenotype. Secondly, we utilized the ROS/MAP Alzheimer's disease dataset (n = 500), consisting of high-throughput measurements of brain tissue to explore modules associated with multiple Alzheimer's Disease-related phenotypes. Our method identifies modules that are multi-omic, span multiple pathways, and vary in size. We provide an interactive tool to explore this hierarchy at different levels and probe enriched modules, empowering users to examine the full hierarchy, delve into biomolecular drivers of disease phenotype within a module, and incorporate functional annotations.
Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Fenótipo , Algoritmos , Biologia Computacional/métodos , Análise por Conglomerados , MultiômicaRESUMO
BACKGROUND: Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. METHODS: To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. RESULTS: Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. CONCLUSION: Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.
Assuntos
Doença de Alzheimer , Encéfalo , Disfunção Cognitiva , Microglia , Animais , Microglia/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Camundongos , Disfunção Cognitiva/metabolismo , Humanos , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Tomografia por Emissão de Pósitrons , Receptores de GABA/metabolismo , Masculino , Camundongos Transgênicos , Conectoma/métodos , FemininoRESUMO
AIMS: Alzheimer's disease (AD) is a neurodegenerative disorder with limited treatment options. This study aimed to investigate the therapeutic effects of Ginkgo biloba leaf extract (GBE) on AD and explore its potential mechanisms of action. METHODS: Key chemical components of GBE, including quercetin, luteolin, and kaempferol, were identified using network pharmacology methods. Bioinformatics analysis revealed their potential roles in AD through modulation of the PI3K/AKT/NF-κB signaling pathway. RESULTS: Mouse experiments demonstrated that GBE improved cognitive function, enhanced neuronal morphology, and reduced serum inflammatory factors. Additionally, GBE modulated the expression of relevant proteins and mRNA. CONCLUSION: GBE shows promise as a potential treatment for AD. Its beneficial effects on cognitive function, neuronal morphology, and inflammation may be attributed to its modulation of the PI3K/AKT/NF-κB signaling pathway. These findings provide experimental evidence for the application of Ginkgo biloba leaf in AD treatment and highlight its potential mechanisms of action.
Assuntos
Doença de Alzheimer , Ginkgo biloba , Extratos Vegetais , Folhas de Planta , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Camundongos , Masculino , Folhas de Planta/química , NF-kappa B/metabolismo , Cognição/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Extrato de GinkgoRESUMO
Impaired clearance of amyloid ß (Aß) in late-onset Alzheimer's disease (AD) affects disease progression. The role of peripheral monocytes in Aß clearance from the central nervous system (CNS) is unclear. We use a flow cytometry assay to identify Aß-binding monocytes in blood, validated by confocal microscopy, Western blotting, and mass spectrometry. Flow cytometry immunophenotyping and correlation with AD biomarkers are studied in 150 participants from the AIBL study. We also examine monocytes in human cerebrospinal fluid (CSF) and their migration in an APP/PS1 mouse model. The assay reveals macrophage-like Aß-binding monocytes with high phagocytic potential in both the periphery and CNS. We find lower surface Aß levels in mild cognitive impairment (MCI) and AD-dementia patients compared to cognitively unimpaired individuals. Monocyte infiltration from blood to CSF and migration from CNS to peripheral lymph nodes and blood are observed. Here we show that Aß-binding monocytes may play a role in CNS Aß clearance, suggesting their potential as a biomarker for AD diagnosis and monitoring.