Porphyromonas gingivalis Outer Membrane Vesicles as the Major Driver of and Explanation for Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis, and Salivary Lactoferrin in Alzheimer’s Disease

Journal of Alzheimer s Disease, Journal Year: 2021, Volume and Issue: 82(4), P. 1417 - 1450

Published: July 16, 2021

Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced "chronic" multi-systems inflammatory disease(s) including Alzheimer's disease (AD). It possibly only second identified unique example of biological extremophile human body. Having better understanding key microbiological and genetic mechanisms its pathogenesis induction are central to future diagnosis, treatment, possible prevention. The published literature around role Pg AD highlights bacteria's direct within brain cause disease. available evidence, although somewhat adopted, does not fully support this as major process. There alternative pathogenic/virulence features associated with that have been overlooked may explain pathogenic processes found "infection hypothesis" AD. A explanation offered here for discrepancy relatively low amounts "Pg bacteria" residing compared rather florid broad distribution one or more bacterial protein toxins. Related this, "Gingipains Hypothesis", AD-related iron dyshomeostasis, early reduced salivary lactoferrin, along resurrection Cholinergic Hypothesis now be integrated into working model. current paper suggests highly evolved developed Type IX secretory cargo system producing outer membrane vesicles observed diseases. Thus it hoped can provide unifying model sporadic form guide direction research,

Language: Английский

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Artificial Intelligence and Precision Medicine: A New Frontier for the Treatment of Brain Tumors

Life, Journal Year: 2022, Volume and Issue: 13(1), P. 24 - 24

Published: Dec. 22, 2022

Brain tumors are a widespread and serious neurological phenomenon that can be life- threatening. The computing field has allowed for the development of artificial intelligence (AI), which mimic neural network human brain. One use this technology been to help researchers capture hidden, high-dimensional images brain tumors. These provide new insights into nature improve treatment options. AI precision medicine (PM) converging revolutionize healthcare. potential cancer imaging interpretation in several ways, including more accurate tumor genotyping, precise delineation volume, better prediction clinical outcomes. AI-assisted surgery an effective safe option treating This review discusses various PM techniques used treatment. tumors, i.e., genomic profiling, microRNA panels, quantitative imaging, radiomics, hold great promise future. However, there challenges must overcome these technologies reach their full

Language: Английский

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Genetic influences on brain and cognitive health and their interactions with cardiovascular conditions and depression

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 18, 2024

Abstract Approximately 40% of dementia cases could be prevented or delayed by modifiable risk factors related to lifestyle and environment. These factors, such as depression vascular disease, do not affect all individuals in the same way, likely due inter-individual differences genetics. However, precise nature how genetic profiles interact with brain health is poorly understood. Here we combine multiple data resources, including genotyping postmortem gene expression, map landscape structure identify 367 loci associated cortical thickness 13 white matter hyperintensities (P < 5×10 −8 ), several also showing a significant association cognitive function. We show that among 220 unique our genome-wide studies (GWAS), 95 showed evidence interaction cardiovascular conditions. Polygenic scores based on GWAS inferior frontal interacted hypertension predicting executive function Canadian Longitudinal Study Aging. findings advance understanding underpinning for part moderated treatable mid-life factors.

Language: Английский

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Bulk and Single-Nucleus Transcriptomics Highlight Intra-Telencephalic and Somatostatin Neurons in Alzheimer’s Disease

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: June 10, 2022

Cortical neuron loss is a pathological hallmark of late-onset Alzheimer’s disease (AD). However, it remains unclear which neuronal subtypes beyond broad excitatory and inhibitory classes are most vulnerable. Here, we analyzed cell subtype proportion differences in AD compared to non-AD controls using 1037 post-mortem brain samples from six neocortical regions. We identified the strongest associations with fewer somatostatin (SST) neurons (β = −0.48, p bonf 8.98 × 10 –9 ) intra-telencephalic (IT) -0.45, 4.32 –7 ). Replication three case-control single-nucleus RNAseq datasets strongly supported bulk tissue association SST AD. In depth analyses type proportions specific AD-related neuropathological cognitive phenotypes revealed greater brain-wide tau beta amyloid, as well faster rate antemortem decline. contrast, IT were associated slower decline residual cognition–a measure resilience–but not canonical neuropathology. Our findings implicate subclasses pathogenesis resilience pathology, respectively.

Language: Английский

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ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer’s disease through BDNF/NGFR signaling

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(9), P. 100642 - 100642

Published: Aug. 30, 2024

Language: Английский

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Integration across biophysical scales identifies molecular and cellular correlates of person-to-person variability in human brain connectivity

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(11), P. 2240 - 2252

Published: Oct. 31, 2024

Brain connectivity arises from interactions across biophysical scales, ranging molecular to cellular anatomical network level. To date, there has been little progress toward integrated analysis these scales. bridge this gap, a unique cohort of 98 individuals, we collected antemortem neuroimaging and genetic data, as well postmortem dendritic spine morphometric, proteomic gene expression data the superior frontal inferior temporal gyri. Through integration morphology identified hundreds proteins that explain interindividual differences in functional structural covariation. These are enriched for synaptic structures functions, energy metabolism RNA processing. By integrating at genetic, molecular, subcellular tissue levels, link specific biochemical changes synapses between brain regions. results demonstrate feasibility vastly different scales provide more comprehensive understanding connectivity. Integration morphological measurements enables detection microscale molecules associated with person-to-person variability macroscale estimated neuroimaging.

Language: Английский

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NCBP2-AS2 is a mitochondrial microprotein, regulates energy metabolism and neurogenesis, and is downregulated in Alzheimer's disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Abstract Microproteins, short functional peptides encoded by small genes, are emerging as critical regulators of cellular processes, yet their roles in mitochondrial function and neurodegeneration remain underexplored. In this study, we identify NCBP2-AS2 an evolutionarily conserved microprotein with significant energy metabolism neurogenesis. Using a combination molecular approaches, including CRISPR/Cas9 knockout models, stoichiometric co- immunoprecipitation, advanced imaging techniques, demonstrate that localizes to the inner space interacts translocase membrane (TIM) chaperones. These interactions suggest role ATPase subunit transport, supported observed reductions levels impaired glucose NCBP2-AS2-deficient cells. zebrafish, led increased astroglial proliferation, microglial abundance, enhanced neurogenesis, particularly under amyloid pathology. Notably, show expression is consistently downregulated human Alzheimer’s disease brains zebrafish amyloidosis suggesting neurodegenerative findings reveal novel link between protein metabolism, neural regeneration, positioning potential therapeutic target for mitigating dysfunction promoting neurogenesis diseases such disease.

Language: Английский

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A single-cell atlas to map sex-specific gene-expression changes in blood upon neurodegeneration

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 25, 2025

Abstract The clinical course and treatment of neurodegenerative disease are complicated by immune-system interference chronic inflammatory processes, which remain incompletely understood. Mapping immune signatures in larger human cohorts through single-cell gene expression profiling supports our understanding observed peripheral changes neurodegeneration. Here, we employ over 909k blood mononuclear cells (PBMCs) from 121 healthy individuals, 48 patients with mild cognitive impairment (MCI), 46 Parkinson’s (PD), 27 Alzheimer’s (AD), 15 both PD MCI. dataset is interactively accessible a freely available website ( https://www.ccb.uni-saarland.de/adrcsc ). In this work, identify disease-associated cell type composition the sex-specific manner, offering insights into solid tissue AD PD.

Language: Английский

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Systematic review and meta‐analysis of bulk RNAseq studies in human Alzheimer's disease brain tissue

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(3)

Published: March 1, 2025

We systematically reviewed and meta-analyzed bulk RNA sequencing (RNAseq) studies comparing Alzheimer's disease (AD) patients to controls in human brain tissue. searched PubMed, Web of Science, Scopus for RNAseq studies, excluding re-analyses limited small RNAs or gene panels. developed 10 criteria quality assessment performed a meta-analysis on three high-quality datasets. Of 3266 records, 24 qualified the systematic review, one study with datasets meta-analysis. The identified 571 differentially expressed genes (DEGs) temporal lobe 189 frontal lobe, including CLU GFAP. Pathway analysis suggested reactivation developmental processes adult AD brain. Limited data availability constrained These findings underscore need rigorous methods transcriptomic research better identify changes advance biomarker therapeutic development. This review is registered PROSPERO (CRD42023466522). Comprehensive review: Conducted first non-demented using primary Identified AD, revealing potential targets. discovery: Highlighted key overlapping pathways such as "tube morphogenesis" "neuroactive ligand-receptor interaction" that may play critical roles AD. Emphasized importance methodological rigor tools guide future Acknowledged access complete tables lack diversity existing datasets, which some analysis.

Language: Английский

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Polygenic Risk Score for Alzheimer's Disease in Caribbean Hispanics

Annals of Neurology, Journal Year: 2021, Volume and Issue: 90(3), P. 366 - 376

Published: May 26, 2021

Polygenic risk scores (PRSs) assess the individual genetic propensity to a condition by combining sparse information scattered across loci, often displaying small effect sizes. Most PRSs are constructed in European-ancestry populations, limiting their use other ethnicities. Here we and validated PRS for late-onset Alzheimer's Disease (LOAD) Caribbean Hispanics (CH).

Language: Английский

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