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INTRODUCTION: A noncoding variant (rs35349669) within INPP5D, a lipid and protein phosphatase restricted to microglia in the brain, is linked to increased susceptibility to Alzheimer's disease (AD). While Inpp5d is well-studied in amyloid pathology, its role in tau pathology remains unclear. METHODS: PS19 Tauopathy mice were crossed with Inpp5d-haplodeficient (Inpp5d+/-) mice to examine the impact of Inpp5d in tau pathology. RESULTS: Increased INPP5D expression correlated positively withâ¯phospho-Tau AT8 in PS19 mice. Inpp5d haplodeficiency mitigated hyperphosphorylated tau levels (AT8, AT180, AT100, and PHF1) and motor deficits in PS19 mice. Transcriptomic analysis revealed an up-regulation of genes associatedâ¯with immune response and cell migration. DISCUSSION: Our findings define an association between INPP5D expression and tau pathology in PS19 mice. Alleviation in hyperphosphorylated tau, motor deficits, and transcriptomics changes in haplodeficient-Inpp5d PS19 mice indicate that modulation in INPP5D expression may provide therapeutic potential for mitigating tau pathology and improving motor deficits. HIGHLIGHTS: The impact of Inpp5d in the context of tau pathology was studied in the PS19 mouse model. INPP5D expression is associated with tau pathology. Reduced Inpp5d expression in PS19 mice improved motor functions and decreased total and phospho-Tau levels. Inpp5d haplodeficiency in PS19 mice modulates gene expression patterns linked to immune response and cell migration. These data suggest that inhibition of Inpp5d may be a therapeutic approach in tauopathies.
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Modelos Animais de Doenças , Camundongos Transgênicos , Tauopatias , Proteínas tau , Animais , Camundongos , Encéfalo/patologia , Encéfalo/metabolismo , Fosforilação , Proteínas tau/metabolismo , Tauopatias/patologia , Tauopatias/metabolismo , Tauopatias/genéticaRESUMO
Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tumors are not sensitive to endocrine therapy, and standardized TNBC treatment regimens are lacking. TNBC is a more immunogenic subtype of breast cancer, making it more responsive to immunotherapy intervention. Tumor-associated macrophages (TAMs) constitute one of the most abundant immune cell populations in TNBC tumors and contribute to cancer metastasis. This study examines the role of the protein kinase HUNK in tumor immunity. Gene expression analysis using NanoString's nCounter PanCancer Immune Profiling panel identified that targeting HUNK is associated with changes in the IL-4/IL-4 R cytokine signaling pathway. Experimental analysis shows that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. In addition, HUNK-dependent regulation of IL-4 secreted from tumor cells induces polarization of macrophages into an M2-like phenotype associated with TAMs. In return, IL-4 induces cancer metastasis and macrophages to produce epidermal growth factor. These findings delineate a paracrine signaling exchange between tumor cells and TAMs regulated by HUNK and dependent on IL-4/IL-4 R. This highlights the potential of HUNK as a target for reducing TNBC metastasis through modulation of the TAM population.
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Interleucina-4 , Neoplasias de Mama Triplo Negativas , Macrófagos Associados a Tumor , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Humanos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Feminino , Animais , Camundongos , Interleucina-4/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Linhagem Celular Tumoral , Transdução de Sinais , Regulação Neoplásica da Expressão Gênica , Receptores de Interleucina-4/metabolismo , Receptores de Interleucina-4/genéticaRESUMO
INTRODUCTION: Inpp5d is genetically associated with Alzheimer's disease risk. Loss of Inpp5d alters amyloid pathology in models of amyloidosis. Inpp5d is expressed predominantly in microglia but its function in brain is poorly understood. METHODS: We performed single-cell RNA sequencing to study the effect of Inpp5d loss on wild-type mouse brain transcriptomes. RESULTS: Loss of Inpp5d has sex-specific effects on the brain transcriptome. Affected genes are enriched for multiple neurodegeneration terms. Network analyses reveal a gene co-expression module centered around Inpp5d in female mice. Inpp5d loss alters Pleotrophin (PTN), Prosaposin (PSAP), and Vascular Endothelial Growth Factor A (VEGFA) signaling probability between cell types. DISCUSSION: Our data suggest that the normal function of Inpp5d is entangled with mechanisms involved in neurodegeneration. We report the effect of Inpp5d loss without pathology and show that this has dramatic effects on gene expression. Our study provides a critical reference for researchers of neurodegeneration, allowing separation of disease-specific changes mediated by Inpp5d in disease from baseline effects of Inpp5d loss. HIGHLIGHTS: Loss of Inpp5d has different effects in male and female mice. Genes dysregulated by Inpp5d loss relate to neurodegeneration. Total loss of Inpp5d in female mice collapses a conserved gene co-expression module. Loss of microglial Inpp5d affects the transcriptome of other cell types.
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INTRODUCTION: MODEL-AD (Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease) is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory and progression of late-onset Alzheimer's disease (LOAD) more accurately. METHODS: We created the LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, and humanized amyloid-beta (Aß). Mice were subjected to a control diet or a high-fat/high-sugar diet (LOAD2+HFD). We assessed disease-relevant outcome measures in plasma and brain including neuroinflammation, Aß, neurodegeneration, neuroimaging, and multi-omics. RESULTS: By 18 months, LOAD2+HFD mice exhibited sex-specific neuron loss, elevated insoluble brain Aß42, increased plasma neurofilament light chain (NfL), and altered gene/protein expression related to lipid metabolism and synaptic function. Imaging showed reductions in brain volume and neurovascular uncoupling. Deficits in acquiring touchscreen-based cognitive tasks were observed. DISCUSSION: The comprehensive characterization of LOAD2+HFD mice reveals that this model is important for preclinical studies seeking to understand disease trajectory and progression of LOAD prior to or independent of amyloid plaques and tau tangles. HIGHLIGHTS: By 18 months, unlike control mice (e.g., LOAD2 mice fed a control diet, CD), LOAD2+HFD mice presented subtle but significant loss of neurons in the cortex, elevated levels of insoluble Ab42 in the brain, and increased plasma neurofilament light chain (NfL). Transcriptomics and proteomics showed changes in gene/proteins relating to a variety of disease-relevant processes including lipid metabolism and synaptic function. In vivo imaging revealed an age-dependent reduction in brain region volume (MRI) and neurovascular uncoupling (PET/CT). LOAD2+HFD mice also demonstrated deficits in acquisition of touchscreen-based cognitive tasks.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Proteínas tau , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Camundongos , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Proteínas tau/genética , Camundongos Transgênicos , Encéfalo/patologia , Encéfalo/metabolismo , Sinapses/patologia , Sinapses/metabolismo , Masculino , Feminino , HumanosRESUMO
Understanding microglial states in the aging brain has become crucial, especially with the discovery of numerous Alzheimer's disease (AD) risk and protective variants in genes such as INPP5D and TREM2, which are essential to microglia function in AD. Here we present a thorough examination of microglia-like cells and primary mouse microglia at the proteome and transcriptome levels to illuminate the roles these genes and the proteins they encode play in various cell states. First, we compared the proteome profiles of wildtype and INPP5D (SHIP1) knockout primary microglia. Our findings revealed significant proteome alterations only in the homozygous SHIP1 knockout, revealing its impact on the microglial proteome. Additionally, we compared the proteome and transcriptome profiles of commonly used in vitro microglia BV2 and HMC3 cells with primary mouse microglia. Our results demonstrated a substantial similarity between the proteome of BV2 and mouse primary cells, while notable differences were observed between BV2 and human HMC3. Lastly, we conducted targeted lipidomic analysis to quantify different phosphatidylinositols (PIs) species, which are direct SHIP1 targets, in the HMC3 and BV2 cells. This in-depth omics analysis of both mouse and human microglia enhances our systematic understanding of these microglia models. SIGNIFICANCE: Given the growing urgency of comprehending microglial function in the context of neurodegenerative diseases and the substantial therapeutic implications associated with SHIP1 modulation, we firmly believe that our study, through a rigorous and comprehensive proteomics, transcriptomics and targeted lipidomic analysis of microglia, contributes to the systematic understanding of microglial function in the context of neurodegenerative diseases.
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Doença de Alzheimer , Microglia , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Proteoma , Microglia/metabolismo , Animais , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Camundongos , Proteoma/metabolismo , Proteoma/análise , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Camundongos Knockout , Transcriptoma , Fosfatidilinositóis/metabolismo , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Proteômica/métodosRESUMO
INTRODUCTION: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. METHODS: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. RESULTS: We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. DISCUSSION: These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics. HIGHLIGHTS: A novel approach to validate genetic risk factors for late-onset AD (LOAD) is presented. LOAD risk variants were knocked in to conserved mouse loci. Variant effects were assayed by transcriptional analysis. Risk variants in Abca7, Mthfr, Plcg2, and Sorl1 loci modeled molecular signatures of clinical disease. This approach should generate more translationally relevant animal models.
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Doença de Alzheimer , Modelos Animais de Doenças , Predisposição Genética para Doença , Camundongos Transgênicos , Doença de Alzheimer/genética , Animais , Camundongos , Humanos , Fatores de Risco , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Masculino , Encéfalo/patologia , Encéfalo/metabolismo , FemininoRESUMO
A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole-sporozoite PfSPZ vaccine in African infants. Innate immune activation and myeloid signatures at prevaccination baseline correlated with protection from P. falciparum parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ vaccine dose. Machine learning identified spliceosome, proteosome, and resting DC signatures as prevaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline circumsporozoite protein-specific (CSP-specific) IgG predicted nonprotection. Prevaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T cell responses after vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naive mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity by whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggests that PfSPZ vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.
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Imunidade Inata , Vacinas Antimaláricas , Malária Falciparum , Plasmodium falciparum , Esporozoítos , Vacinas Atenuadas , Vacinas Antimaláricas/imunologia , Vacinas Antimaláricas/administração & dosagem , Imunidade Inata/imunologia , Humanos , Animais , Malária Falciparum/prevenção & controle , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Camundongos , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/administração & dosagem , Esporozoítos/imunologia , Esporozoítos/efeitos da radiação , Linfócitos T CD8-Positivos/imunologia , Lactente , Proteínas de Protozoários/imunologia , Anticorpos Antiprotozoários/imunologia , Feminino , Parasitemia/imunologia , Parasitemia/prevenção & controle , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Eficácia de VacinasRESUMO
INTRODUCTION: Ozone (O3) is an air pollutant associated with Alzheimer's disease (AD) risk. The lung-brain axis is implicated in O3-associated glial and amyloid pathobiology; however, the role of disease-associated astrocytes (DAAs) in this process remains unknown. METHODS: The O3-induced astrocyte phenotype was characterized in 5xFAD mice by spatial transcriptomics and proteomics. Hmgb1fl/fl LysM-Cre+ mice were used to assess the role of peripheral myeloid cell high mobility group box 1 (HMGB1). RESULTS: O3 increased astrocyte and plaque numbers, impeded the astrocyte proteomic response to plaque deposition, augmented the DAA transcriptional fingerprint, increased astrocyte-microglia contact, and reduced bronchoalveolar lavage immune cell HMGB1 expression in 5xFAD mice. O3-exposed Hmgb1fl/fl LysM-Cre+ mice exhibited dysregulated DAA mRNA markers. DISCUSSION: Astrocytes and peripheral myeloid cells are critical lung-brain axis interactors. HMGB1 loss in peripheral myeloid cells regulates the O3-induced DAA phenotype. These findings demonstrate a mechanism and potential intervention target for air pollution-induced AD pathobiology. HIGHLIGHTS: Astrocytes are part of the lung-brain axis, regulating how air pollution affects plaque pathology. Ozone (O3) astrocyte effects are associated with increased plaques and modified by plaque localization. O3 uniquely disrupts the astrocyte transcriptomic and proteomic disease-associated astrocyte (DAA) phenotype in plaque associated astrocytes (PAA). O3 changes the PAA cell contact with microglia and cell-cell communication gene expression. Peripheral myeloid cell high mobility group box 1 regulates O3-induced transcriptomic changes in the DAA phenotype.
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Doença de Alzheimer , Astrócitos , Proteína HMGB1 , Ozônio , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Proteína HMGB1/metabolismo , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Camundongos Transgênicos , Modelos Animais de Doenças , Encéfalo/patologia , Encéfalo/metabolismo , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Microglia/metabolismo , Poluentes Atmosféricos , Pulmão/patologia , Peptídeos beta-Amiloides/metabolismoRESUMO
INTRODUCTION: Genetic studies conducted over the past four decades have provided us with a detailed catalog of genes that play critical roles in the etiology of Alzheimer's disease (AD) and related dementias (ADRDs). Despite this progress, as a field we have had only limited success in incorporating this rich complexity of human AD/ADRD genetics findings into our animal models of these diseases. Our primary goal for the gene replacement (GR)-AD project is to develop mouse lines that model the genetics of AD/ADRD as closely as possible. METHODS: To do this, we are generating mouse lines in which the genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs. RESULTS: Each model set consists of a control line with a wild-type human allele and variant lines that precisely match the human genomic sequence in the control line except for a high-impact pathogenic mutation or risk variant.
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Doença de Alzheimer , Humanos , Animais , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Proteínas tau/genética , Mutação , Presenilina-1/genética , Precursor de Proteína beta-Amiloide/genéticaRESUMO
PURPOSE OF REVIEW: This comprehensive review delves into the intricate interplay between Alzheimer's disease (AD) and osteoporosis, two prevalent conditions with significant implications for individuals' quality of life. The purpose is to explore their bidirectional association, underpinned by common pathological processes such as aging, genetic factors, inflammation, and estrogen deficiency. RECENT FINDINGS: Recent advances have shown promise in treating both Alzheimer's disease (AD) and osteoporosis by targeting disease-specific proteins and bone metabolism regulators. Monoclonal antibodies against beta-amyloid and tau for AD, as well as RANKL and sclerostin for osteoporosis, have displayed therapeutic potential. Additionally, ongoing research has identified neuroinflammatory genes shared between AD and osteoporosis, offering insight into the interconnected inflammatory mechanisms. This knowledge opens avenues for innovative dual-purpose therapies that could address both conditions, potentially revolutionizing treatment approaches for AD and osteoporosis simultaneously. This review underscores the potential for groundbreaking advancements in early diagnosis and treatment by unraveling the intricate connection between AD and bone health. It advocates for a holistic, patient-centered approach to medical care that considers both cognitive and bone health, ultimately aiming to enhance the overall well-being of individuals affected by these conditions. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.
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Doença de Alzheimer , Osteoporose , Humanos , Doença de Alzheimer/terapia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Inteligência Artificial , Qualidade de Vida , Peptídeos beta-Amiloides , Osteoporose/terapiaRESUMO
Human epidermal growth factor receptor 2 (HER2)-targeted agents have proven to be effective, however, the development of resistance to these agents has become an obstacle in treating HER2+ breast cancer. Evidence implicates HUNK as an anti-cancer target for primary and resistant HER2+ breast cancers. In this study, a selective inhibitor of HUNK is characterized alongside a phosphorylation event in a downstream substrate of HUNK as a marker for HUNK activity in HER2+ breast cancer. Rubicon has been established as a substrate of HUNK that is phosphorylated at serine (S) 92. Findings indicate that HUNK-mediated phosphorylation of Rubicon at S92 promotes both autophagy and tumorigenesis in HER2/neu+ breast cancer. HUNK inhibition prevents Rubicon S92 phosphorylation in HER2/neu+ breast cancer models and inhibits tumorigenesis. This study characterizes a downstream phosphorylation event as a measure of HUNK activity and identifies a selective HUNK inhibitor that has meaningful efficacy toward HER2+ breast cancer.
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Antineoplásicos , Neoplasias da Mama , Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Receptor ErbB-2 , Animais , Feminino , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Relação Estrutura-Atividade , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Relacionadas à Autofagia/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: This review examines the linked pathophysiology of Alzheimer's disease/related dementia (AD/ADRD) and bone disorders like osteoporosis. The emphasis is on "inflammaging"-a low-level inflammation common to both, and its implications in an aging population. RECENT FINDINGS: Aging intensifies both ADRD and bone deterioration. Notably, ADRD patients have a heightened fracture risk, impacting morbidity and mortality, though it is uncertain if fractures worsen ADRD. Therapeutically, agents targeting inflammation pathways, especially Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and TNF-α, appear beneficial for both conditions. Additionally, treatments like Sirtuin 1 (SIRT-1), known for anti-inflammatory and neuroprotective properties, are gaining attention. The interconnectedness of AD/ADRD and bone health necessitates a unified treatment approach. By addressing shared mechanisms, we can potentially transform therapeutic strategies, enriching our understanding and refining care in our aging society. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.
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Doença de Alzheimer , Demência , Humanos , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/terapia , Demência/epidemiologia , Demência/terapia , Inteligência Artificial , Densidade Óssea , InflamaçãoRESUMO
Amyloid-ß (Aß) and tau proteins accumulate within distinct neuronal systems in Alzheimer's disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aß and tau pathologies than others, gene expression may play a role. We study the association between brain-wide gene expression profiles and regional vulnerability to Aß (gene-to-Aß associations) and tau (gene-to-tau associations) pathologies by leveraging two large independent AD cohorts. We identify AD susceptibility genes and gene modules in a gene co-expression network with expression profiles specifically related to regional vulnerability to Aß and tau pathologies in AD. In addition, we identify distinct biochemical pathways associated with the gene-to-Aß and the gene-to-tau associations. These findings may explain the discordance between regional Aß and tau pathologies. Finally, we propose an analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Transcriptoma/genética , Doença de Alzheimer/genética , Perfilação da Expressão Gênica , Peptídeos beta-Amiloides , Disfunção Cognitiva/genéticaRESUMO
BACKGROUND: Periodontitis is a chronic inflammatory disease defined by the pathologic loss of the periodontal ligament and alveolar bone in relation to aging. Although clinical cohort studies reported that periodontitis is significantly elevated in males compared to females, emerging evidence indicates that females with dementia are at a greater risk for periodontitis and decreased alveolar bone. OBJECTIVE: This study aimed to evaluate whether dementia is a potential sex-dependent risk factor for periodontal bone loss using an experimental model of periodontitis induced in the triple transgenic (3x-Tg) dementia-like mice and clinical samples collected from senior 65 plus age patients with diagnosed dementia. MATERIALS AND METHODS: We induced periodontitis in dementia-like triple-transgenic (3x-Tg) male and female mice and age-matched wild-type (WT) control mice by ligature placement. Then, alveolar bone loss and osteoclast activity were evaluated using micro-CT and in situ imaging assays. In addition, we performed dental examinations on patients with diagnosed dementia. Finally, dementia-associated Aß42 and p-Tau (T181) and osteoclastogenic receptor activator of nuclear factor kappa-Β ligand (RANKL) in gingival crevicular fluid (GCF) collected from mice and clinical samples were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Alveolar bone loss and in situ osteoclast activity were significantly elevated in periodontal lesions of 3x-Tg females but not males, compared to wild-type control mice. In addition, we also observed that the probing pocket depth (PPD) was also significantly elevated in female patients with dementia. Using ELISA assay, we observed that females had elevated levels of osteoclastogenic RANKL and dementia-associated Aß42 and p-Tau (T181) in the GCF collected from experimental periodontitis lesions and clinical samples. CONCLUSION: Altogether, we demonstrate that females with dementia have an increased risk for periodontal bone loss compared to males.
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Perda do Osso Alveolar , Demência , Modelos Animais de Doenças , Camundongos Transgênicos , Periodontite , Ligante RANK , Animais , Feminino , Perda do Osso Alveolar/patologia , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/metabolismo , Masculino , Camundongos , Demência/etiologia , Humanos , Idoso , Ligante RANK/análise , Ligante RANK/metabolismo , Fatores Sexuais , Periodontite/complicações , Periodontite/patologia , Microtomografia por Raio-X , Osteoclastos/patologia , Peptídeos beta-Amiloides/metabolismo , Líquido do Sulco Gengival/química , Fragmentos de Peptídeos/análise , Fatores de RiscoRESUMO
PURPOSE OF REVIEW: This Comment represents three review articles on the relationship between Alzheimer's disease, osteoporosis, and fracture in an exploration of the benefits that AI can provide in scientific writing. The first drafts of the articles were written (1) entirely by humans; (2) entirely by ChatGPT 4.0 (AI-only or AIO); and (3) by humans and ChatGPT 4.0 whereby humans selected literature references, but ChatGPT 4.0 completed the writing (AI-assisted or AIA). Importantly, each review article was edited and carefully checked for accuracy by all co-authors resulting in a final manuscript which was significantly different from the original draft. RECENT FINDINGS: The human-written article took the most time from start to finish, the AI-only article took the least time, and the AI-assisted article fell between the two. When comparing first drafts to final drafts, the AI-only and AI-assisted articles had higher percentages of different text than the human article. The AI-only paper had a higher percentage of incorrect references in the first draft than the AI-assisted paper. The first draft of the AI-assisted article had a higher similarity score than the other two articles when examined by plagiarism identification software. This writing experiment used time tracking, human editing, and comparison software to examine the benefits and risks of using AI to assist in scientific writing. It showed that while AI may reduce total writing time, hallucinations and plagiarism were prevalent issues with this method and human editing was still necessary to ensure accuracy.
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Doença de Alzheimer , Fraturas Ósseas , Humanos , Idioma , Redação , Inteligência ArtificialRESUMO
PURPOSE OF REVIEW: This comprehensive review discusses the complex relationship between Alzheimer's disease (AD) and osteoporosis, two conditions that are prevalent in the aging population and result in adverse complications on quality of life. The purpose of this review is to succinctly elucidate the many commonalities between the two conditions, including shared pathways, inflammatory and oxidative mechanisms, and hormonal deficiencies. RECENT FINDINGS: AD and osteoporosis share many aspects of their respective disease-defining pathophysiology. These commonalities include amyloid beta deposition, the Wnt/ß-catenin signaling pathway, and estrogen deficiency. The shared mechanisms and risk factors associated with AD and osteoporosis result in a large percentage of patients that develop both diseases. Previous literature has established that the progression of AD increases the risk of sustaining a fracture. Recent findings demonstrate that the reverse may also be true, suggesting that a fracture early in the life course can predispose one to developing AD due to the activation of these shared mechanisms. The discovery of these commonalities further guides the development of novel therapeutics in which both conditions are targeted. This detailed review delves into the commonalities between AD and osteoporosis to uncover the shared players that bring these two seemingly unrelated conditions together. The discussion throughout this review ultimately posits that the occurrence of fractures and the mechanism behind fracture healing can predispose one to developing AD later on in life, similar to how AD patients are at an increased risk of developing fractures. By focusing on the shared mechanisms between AD and osteoporosis, one can better understand the conditions individually and as a unit, thus informing therapeutic approaches and further research. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.
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Connexin 43 (Cx43) is a protein encoded by the GJA1 gene and is a component of cell membrane structures called gap junctions, which facilitate intercellular communication. Prior evidence indicates that elevated GJA1 expression in the HER2-positive (HER2+) subtype of breast cancer is associated with poor prognosis. Prior evidence also suggests that HER2+ breast cancers that have become refractory to HER2-targeted agents have a loss of Cx43 gap junction intercellular communication (GJIC). In this study, a Cx43-targeted agent called alpha-connexin carboxyl-terminal peptide (aCT1) is examined to determine whether GJIC can be rescued in refractory HER2+ breast cancer cells. A proposed mechanism of action for aCT1 is binding to the tight junction protein Zonal Occludens-1 (ZO-1). However, the true scope of activity for aCT1 has not been explored. In this study, mass spectrometry proteomic analysis is used to determine the breadth of aCT1-interacting proteins. The NanoString nCounter Breast Cancer 360 panel is also used to examine the effect of aCT1 on cancer signaling in HER2+ breast cancer cells. Findings from this study show a dynamic range of binding partners for aCT1, many of which regulate gene expression and RNA biology. nCounter analysis shows that a number of pathways are significantly impacted by aCT1, including upregulation of apoptotic factors, leading to the prediction and demonstration that aCT1 can boost the cell death effects of cisplatin and lapatinib in HER2+ breast cancer cells that have become resistant to HER2-targeted agents.
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INTRODUCTION: The risk of developing Alzheimer's disease is associated with genes involved in microglial function. Inositol polyphosphate-5-phosphatase (INPP5D), which encodes Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1), is a risk gene expressed in microglia. Because SHIP1 binds receptor immunoreceptor tyrosine-based inhibitory motifs (ITIMs), competes with kinases, and converts PI(3,4,5)P3 to PI(3,4)P2, it is a negative regulator of microglia function. Validated inhibitors are needed to evaluate SHIP1 as a potential therapeutic target. METHODS: We identified inhibitors and screened the enzymatic domain of SHIP1. A protein construct containing two domains was used to evaluate enzyme inhibitor potency and selectivity versus SHIP2. Inhibitors were tested against a construct containing all ordered domains of the human and mouse proteins. A cellular thermal shift assay (CETSA) provided evidence of target engagement in cells. Phospho-AKT levels provided further evidence of on-target pharmacology. A high-content imaging assay was used to study the pharmacology of SHIP1 inhibition while monitoring cell health. Physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties were evaluated to select a compound suitable for in vivo studies. RESULTS: SHIP1 inhibitors displayed a remarkable array of activities and cellular pharmacology. Inhibitory potency was dependent on the protein construct used to assess enzymatic activity. Some inhibitors failed to engage the target in cells. Inhibitors that were active in the CETSA consistently destabilized the protein and reduced pAKT levels. Many SHIP1 inhibitors were cytotoxic either at high concentration due to cell stress or they potently induced cell death depending on the compound and cell type. One compound activated microglia, inducing phagocytosis at concentrations that did not result in significant cell death. A pharmacokinetic study demonstrated brain exposures in mice upon oral administration. DISCUSSION: 3-((2,4-Dichlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl) pyridine activated primary mouse microglia and demonstrated exposures in mouse brain upon oral dosing. Although this compound is our recommended chemical probe for investigating the pharmacology of SHIP1 inhibition at this time, further optimization is required for clinical studies. Highlights: Cellular thermal shift assay (CETSA) and signaling (pAKT) assays were developed to provide evidence of src homology 2 (SH2) domain-contaning inositol phosphatase 1 (SHIP1) target engagement and on-target activity in cellular assays.A phenotypic high-content imaging assay with simultaneous measures of phagocytosis, cell number, and nuclear intensity was developed to explore cellular pharmacology and monitor cell health.SHIP1 inhibitors demonstrate a wide range of activity and cellular pharmacology, and many reported inhibitors are cytotoxic.The chemical probe 3-((2,4-dichlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl) pyridine is recommended to explore SHIP1 pharmacology.
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Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aß clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.
Assuntos
Doença de Alzheimer , Animais , Camundongos , Doença de Alzheimer/genética , Estudos de Associação Genética , Microglia , Fagocitose/genética , Fenótipo , Placa Amiloide , Fosfolipase C gama/metabolismoRESUMO
Hallmark features of Alzheimer's disease (AD) include elevated accumulation of aggregated Aß40 and Aß42 peptides, hyperphosphorylated Tau (p-Tau), and neuroinflammation. Emerging evidence indicated that interleukin-34 (IL-34) contributes to AD and inflammatory osteolysis via the colony-stimulating factor-1 receptor (CSF-1r). In addition, CSF-1r is also activated by macrophage colony-stimulating factor-1 (M-CSF). While the role of M-CSF in bone physiology and pathology is well addressed, it remains controversial whether IL-34-mediated signaling promotes osteolysis, neurodegeneration, and neuroinflammation in relation to AD. In this study, we injected 3x-Tg mice with mouse recombinant IL-34 protein over the calvaria bone every other day for 42 days. Then, behavioral changes, brain pathology, and calvaria osteolysis were evaluated using various behavioral maze and histological assays. We demonstrated that IL-34 administration dramatically elevated AD-like anxiety and memory loss, pathogenic amyloidogenesis, p-Tau, and RAGE expression in female 3x-Tg mice. Furthermore, IL-34 delivery promoted calvaria inflammatory osteolysis compared to the control group. In addition, we also compared the effects of IL-34 and M-CSF on macrophages, microglia, and RANKL-mediated osteoclastogenesis in relation to AD pathology in vitro. We observed that IL-34-exposed SIM-A9 microglia and 3x-Tg bone marrow-derived macrophages released significantly elevated amounts of pro-inflammatory cytokines, TNF-α, IL-1ß, and IL-6, compared to M-CSF treatment in vitro. Furthermore, IL-34, but not M-CSF, elevated RANKL-primed osteoclastogenesis in the presence of Aß40 and Aß42 peptides in bone marrow derived macrophages isolated from female 3x-Tg mice. Collectively, our data indicated that IL-34 elevates AD-like features, including behavioral changes and neuroinflammation, as well as osteoclastogenesis in female 3x-Tg mice.