Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)
Published: Oct. 8, 2024
Heparin binding proteins (HBPs) with roles in extracellular matrix assembly are strongly correlated to β-amyloid (Aβ) and tau pathology Alzheimer's disease (AD) brain cerebrospinal fluid (CSF). However, it remains challenging detect these plasma using standard mass spectrometry-based proteomic approaches.
Language: Английский
Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)
Published: Aug. 12, 2021
Mass spectrometry-based proteomics empowers deep profiling of proteome and protein posttranslational modifications (PTMs) in Alzheimer's disease (AD). Here we review the advances limitations historic recent AD proteomic research. Complementary to genetic mapping, studies not only validate canonical amyloid tau pathways, but also uncover novel components broad networks, such as RNA splicing, development, immunity, membrane transport, lipid metabolism, synaptic function, mitochondrial activity. Meta-analysis seven datasets reveals 2,698 differentially expressed (DE) proteins landscape brain (n = 12,017 proteins/genes), covering 35 reported genes risk loci. The DE contain cellular markers enriched neurons, microglia, astrocytes, oligodendrocytes, epithelial cells, supporting involvement diverse cell types pathology. We discuss hypothesized protective or detrimental roles selected proteins, emphasizing top "amyloidome" (all biomolecules plaques) progression. Comprehensive PTM analysis represents another layer molecular events AD. In particular, PTMs are correlated with stages indicate heterogeneity individual patients. Moreover, unprecedented coverage biofluids, cerebrospinal fluid serum, procures putative biomarkers through meta-analysis. Thus, proteomics-driven systems biology presents a new frontier link genotype, proteotype, phenotype, accelerating development improved models treatment strategies.
Language: Английский
Citations
167
Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)
Published: July 25, 2023
Abstract Proteomic studies of human Alzheimer’s disease brain tissue have potential to identify protein changes that drive disease, and new drug targets. Here, we analyse 38 published proteomic studies, generating a map in across thirteen regions, three stages (preclinical mild cognitive impairment, advanced disease), proteins enriched amyloid plaques, neurofibrillary tangles, cerebral angiopathy. Our dataset is compiled into searchable database (NeuroPro). We found 848 were consistently altered 5 or more studies. Comparison early-stage revealed associated with synapse, vesicle, lysosomal pathways show change early but widespread mitochondrial expression are only seen disease. Protein similar for regions considered vulnerable resistant. This resource provides insight highlights interest further study.
Language: Английский
Citations
82
MedComm, Journal Year: 2024, Volume and Issue: 5(2)
Published: Feb. 1, 2024
Cholesterol homeostasis is crucial for cellular and systemic function. The disorder of cholesterol metabolism not only accelerates the onset cardiovascular disease (CVD) but also fundamental cause other ailments. regulation in human an extremely complex process. Due to dynamic balance between synthesis, intake, efflux storage, generally remains secure. Disruption any these links likely have adverse effects on body. At present, increasing evidence suggests that abnormal closely related various diseases. However, exact mechanism by which contributes pathogenesis unclear, there are still unknown factors. In this review, we outline metabolic process body, especially reverse transport (RCT). Then, discuss separately impact common diseases potential therapeutic targets each disease, including CVD, tumors, neurological diseases, immune system end focus effect eye short, hope provide more new ideas treatment from perspective cholesterol.
Language: Английский
Citations
26
Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)
Published: April 1, 2024
Abstract Dysfunction in fast-spiking parvalbumin interneurons (PV-INs) may represent an early pathophysiological perturbation Alzheimer’s Disease (AD). Defining proteomic alterations PV-INs can provide key biological and translationally-relevant insights. We used cell-type-specific in-vivo biotinylation of proteins (CIBOP) coupled with mass spectrometry to obtain native-state PV-IN proteomes. signatures include high metabolic translational activity, over-representation AD-risk cognitive resilience-related proteins. In bulk proteomes, were associated decline humans, progressive neuropathology humans the 5xFAD mouse model Aβ pathology. CIBOP stages pathology revealed increased mitochondria metabolism, synaptic cytoskeletal disruption decreased mTOR signaling, not apparent whole-brain Furthermore, we demonstrated pre-synaptic defects PV-to-excitatory neurotransmission, validating our findings. Overall, this study present proteomes PV-INs, revealing molecular insights into their unique roles resiliency AD pathogenesis.
Language: Английский
Citations
23
Genes, Journal Year: 2025, Volume and Issue: 16(2), P. 135 - 135
Published: Jan. 24, 2025
Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s (PD), Huntington’s (HD), and amyotrophic lateral sclerosis (ALS), represent a growing societal challenge due to their irreversible progression significant impact on patients, caregivers, healthcare systems. Despite advances in clinical imaging-based diagnostics, these diseases are often detected at advanced stages, limiting the effectiveness of therapeutic interventions. Recent breakthroughs genomic transcriptomic technologies, including whole-genome sequencing, single-cell RNA sequencing (scRNA-seq), CRISPR-based screens, have revolutionized field, offering new avenues for early diagnosis personalized prognosis. Genomic approaches elucidated disease-specific genetic risk factors molecular pathways, while studies identified stage-specific biomarkers that correlate with severity. Furthermore, genome-wide association (GWAS), polygenic scores (PRS), spatial transcriptomics enabling stratification patients based profiles prognostic trajectories. Advances functional genomics uncovered actionable targets, ATXN2 ALS TREM2 AD, paving way tailored strategies. achievements, challenges remain translating discoveries into practice heterogeneity complexity neurodegenerative pathophysiology. Future integration technologies holds promise transforming diagnostic paradigms, hope improved patient outcomes precision medicine approaches.
Language: Английский
Citations
2
Annals of Neurosciences, Journal Year: 2021, Volume and Issue: 28(3-4), P. 191 - 200
Published: July 1, 2021
Background: Innate immunity is mediated by a variety of cell types, including microglia, macrophages, and neutrophils, serves as the immune system's first line defense. There are numerous pathways involved in innate immunity, interferon (IFN) pathway, TRK mitogen-activated protein kinase (MAPK) Janus kinase/signal transducer activator transcription (JAK/STAT) interleukin (IL) pathways, chemokine (CCR5), GSK signaling, Fas signaling. Summary: JAK/STAT one these important signaling this review focused on pathway only. The overactivation microglia astrocytes influences JAK/STAT's role neuroinflammatory disease initiating orchestrating adaptive mechanisms, ultimately constraining inflammatory immunological responses. critical factors that promotes neuroinflammation neurodegenerative diseases. Key message: Given importance disease, discussed feasibility targeting neuroprotective therapy for diseases near future.
Language: Английский
Citations
104
Antioxidants, Journal Year: 2021, Volume and Issue: 10(9), P. 1353 - 1353
Published: Aug. 26, 2021
Alzheimer’s disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing leading cause death worldwide the global ageing population. The lack effective treatments overt AD urges discovery biomarkers early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. brain exposed to oxidative stress as levels reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses decreased. Increased ROS can damage structures molecules, protein, lipid, DNA, RNA oxidation. Oxidative involved molecular mechanisms which link accumulation amyloid-β neurofibrillary tangles, containing hyperphosphorylated tau, microglia response. In this scenario, thought play crucial role not only events pathogenesis but also progression disease. This review will focus on products possible peripheral preclinical phases Particular attention be paid biological fluids such blood, CSF, urine, saliva, potential future use molecules contained body differential diagnosis monitoring course. We and, more broadly, neurodegeneration.
Language: Английский
Citations
98
Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 70, P. 101417 - 101417
Published: July 31, 2021
Language: Английский
Citations
72
Scientific Data, Journal Year: 2023, Volume and Issue: 10(1)
Published: May 9, 2023
Abstract Alzheimer’s disease (AD) is the most common form of dementia, with cerebrospinal fluid (CSF) β-amyloid (Aβ), total Tau, and phosphorylated Tau (pTau) providing sensitive specific biomarkers for diagnosis. However, these diagnostic do not reflect complex changes in AD brain beyond amyloid (A) (T) pathologies. Here, we report a selected reaction monitoring mass spectrometry (SRM-MS) method isotopically labeled standards relative protein quantification CSF. Biomarker positive (AT+) negative (AT−) CSF pools were used as quality controls (QCs) to assess assay precision. We detected 62 peptides (51 proteins) an average coefficient variation (CV) ~13% across 30 QCs 133 (cognitively normal, AT−), 127 asymptomatic AT+) 130 symptomatic impaired, AT+). Proteins that could distinguish AT+ from AT− individuals included SMOC1, GDA, 14-3-3 proteins, those involved glycolysis. cognitive impairment mainly neuronal proteins (VGF, NPTX2, NPTXR, SCG2). This demonstrates utility SRM-MS quantify stages AD.
Language: Английский
Citations
35
Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(9), P. 3966 - 3981
Published: Sept. 1, 2023
Accumulation of amyloid β-peptide (Aβ) is a driver Alzheimer's disease (AD). Amyloid precursor protein (App) knock-in mouse models recapitulate AD-associated Aβ pathology, allowing elucidation downstream effects accumulation and their temporal appearance upon progression. Here we have investigated the sequential onset AD-like pathologies in AppNL-F AppNL-G-F mice by time-course transcriptome analysis hippocampus, region severely affected AD. Strikingly, energy metabolism emerged as one most significantly altered pathways already at an early stage pathology. Functional experiments isolated mitochondria from hippocampus both confirmed upregulation oxidative phosphorylation driven activity mitochondrial complexes I, IV V, associated with higher susceptibility to damage Ca2+-overload. Upon increasing pathologies, brain shifts state hypometabolism reduced abundancy presynaptic terminals. These late-stage also displayed enlarged areas abnormal synaptic vesicles autophagosomes, latter ultimately leading local autophagy impairment synapses. In summary, report that Aβ-induced App key observed AD brain, our data herein adds comprehensive understanding including dysregulated synapses timewise find new therapeutic approaches for
Language: Английский
Citations
35