Large-scale deep multi-layer analysis of Alzheimer’s disease brain reveals strong proteomic disease-related changes not observed at the RNA level

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(2), P. 213 - 225

Published: Feb. 1, 2022

The biological processes that are disrupted in the Alzheimer's disease (AD) brain remain incompletely understood. In this study, we analyzed proteomes of more than 1,000 tissues to reveal new AD-related protein co-expression modules were highly preserved across cohorts and regions. Nearly half modules, including significantly altered AD, not observed RNA networks from same regions, highlighting proteopathic nature AD. Two such AD-associated unique proteomic network included a module related MAPK signaling metabolism matrisome. matrisome was influenced by APOE ε4 allele but rate cognitive decline after adjustment for neuropathology. By contrast, MAPK/metabolism strongly associated with decline. Disease-associated proteome sources promising therapeutic targets biomarkers

Language: Английский

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Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia

Neuron, Journal Year: 2021, Volume and Issue: 109(10), P. 1657 - 1674.e7

Published: April 7, 2021

Language: Английский

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Proteomic landscape of Alzheimer’s Disease: novel insights into pathogenesis and biomarker discovery

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

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Mesenchymal stem cell-derived extracellular vesicles ameliorate Alzheimer's disease-like phenotypes in a preclinical mouse model

Theranostics, Journal Year: 2021, Volume and Issue: 11(17), P. 8129 - 8142

Published: Jan. 1, 2021

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder that affects more than 44 million people worldwide. Despite the high burden, there no effective treatment for suffering from AD. Mesenchymal stem cells (MSCs) are multipotent stromal have been widely studied due to their therapeutic potential. However, administration of has found a multitude limitations. Recently, extracellular vesicles (EVs) derived MSCs as candidate, they exhibit similar immunoprotective and immunomodulatory abilities host human MSCs. Methods: To test potential effects MSC EVs, bone-marrow were grown in three-dimensional (3D) cell culture, small EVs harvested using differential ultracentrifugation. These given non-transgenic (NT) or 5XFAD (5 familial mutations) mice intranasally (IN) every 4 days months. The then required perform variety behavioral assays measure changes learning memory. Afterwards, immunohistochemistry was performed on brain slices amyloid beta (Aβ) glial fibrillary acidic protein (GFAP) levels. Results: data revealed received hMSC-EV behaved significantly better cognitive tests saline treated mice, with significant change between EV-treated NT mice. Additionally, we lower Aβ plaque load hippocampus Finally, less colocalization GFAP plaques compared saline. Conclusions: Taken together, these suggest IN MSC-derived can slow down AD pathogenesis.

Language: Английский

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Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 2, 2023

Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on backbones amino acid side chains proteins and expand diversity proteins, which provides basis for emergence organismal complexity. To date, more than 650 types protein modifications, such as most well-known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short-chain long-chain acylation redox irreversible have been described, inventory is still increasing. By changing conformation, localization, activity, stability, charges, interactions with other biomolecules, PTMs ultimately alter phenotypes biological processes cells. The homeostasis important human health. Abnormal may cause changes in properties loss functions, are closely related occurrence development various diseases. In this review, we systematically introduce characteristics, regulatory mechanisms, functions health addition, therapeutic prospects diseases by targeting associated enzymes also summarized. This work will deepen understanding promote discovery diagnostic prognostic markers drug targets

Language: Английский

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Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 51(2), P. 513 - 565

Published: Dec. 10, 2021

We discuss novel approaches for embracing and reproducing complexity of Tau pathology required developing disease-relevant diagnostics effective therapies.

Language: Английский

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The amyloid plaque proteome in early onset Alzheimer’s disease and Down syndrome

Acta Neuropathologica Communications, Journal Year: 2022, Volume and Issue: 10(1)

Published: April 13, 2022

Amyloid plaques contain many proteins in addition to beta amyloid (Aβ). Previous studies examining plaque-associated have shown these additional are important; they provide insight into the factors that drive plaque development and potential biomarkers or therapeutic targets for Alzheimer's disease (AD). The aim of this study was comprehensively identify enriched using unbiased proteomics two subtypes early onset AD: sporadic AD (EOAD) Down Syndrome (DS) with AD. We focused our on as drivers more aggressive pathology cases is unknown it unclear whether amyloid-plaque differ between neighbouring non-plaque tissue were microdissected from human brain sections laser capture microdissection label-free LC-MS used quantify present. 48 consistently EOAD DS. Many significantly than Aβ. most both DS were: COL25A1, SMOC1, MDK, NTN1, OLFML3 HTRA1. Endosomal/lysosomal particularly highly plaques. Fluorescent immunohistochemistry validate enrichment four (moesin, ezrin, ARL8B SMOC1) compare amount total Aβ, Aβ40, Aβ42, phosphorylated pyroglutamate Aβ species oligomeric These showed SMOC1 higher plaques, while oligomers EOAD. Overall, we observed largely contained same proteins, however some different Our highlights significant which may be and/or

Language: Английский

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Compilation of reported protein changes in the brain in Alzheimer’s disease

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

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Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: June 8, 2023

Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Multiple genetic factors have linked to lysosomal de-acidification through impairing vacuolar-type ATPase ion channels on organelle membrane. Similar abnormalities are also present sporadic forms neurodegeneration, although underlying pathogenic mechanisms unclear remain be investigated. Importantly, recent studies revealed early occurrence impairment before onset neurodegeneration late-stage pathology. However, there is lack methods for pH monitoring vivo dearth lysosome-acidifying therapeutic agents. Here, we summarize evidence notion defective an indicator urge critical need technological advancement developing tools detection both clinical applications. We further discuss current preclinical pharmacological agents that modulate acidification, small molecules nanomedicine, their potential translation into lysosome-targeting therapies. Both timely development therapeutics restore function represent paradigm shifts targeting diseases.

Language: Английский

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A comprehensive review of multi-target directed ligands in the treatment of Alzheimer’s disease

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 144, P. 107152 - 107152

Published: Jan. 27, 2024

Language: Английский

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