A new era for understanding amyloid structures and disease

Nature Reviews Molecular Cell Biology, Journal Year: 2018, Volume and Issue: 19(12), P. 755 - 773

Published: Sept. 20, 2018

Language: Английский

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Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation

Nature Medicine, Journal Year: 2020, Volume and Issue: 26(5), P. 769 - 780

Published: April 13, 2020

Language: Английский

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Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways

Nature Reviews Neurology, Journal Year: 2019, Volume and Issue: 16(1), P. 30 - 42

Published: Dec. 11, 2019

Language: Английский

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Four distinct trajectories of tau deposition identified in Alzheimer’s disease

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(5), P. 871 - 881

Published: April 29, 2021

Language: Английский

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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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Phosphorylated tau interactome in the human Alzheimer’s disease brain

Brain, Journal Year: 2020, Volume and Issue: 143(9), P. 2803 - 2817

Published: June 23, 2020

Accumulation of phosphorylated tau is a key pathological feature Alzheimer's disease. Phosphorylated accumulation causes synaptic impairment, neuronal dysfunction and formation neurofibrillary tangles. The actions are mediated by surrounding proteins; however, comprehensive understanding the proteins that interacts with in disease surprisingly limited. Therefore, aim this study was to determine interactome. To end, we used two complementary proteomics approaches: (i) quantitative performed on tangles microdissected from patients advanced disease; (ii) affinity purification-mass spectrometry identify which these specifically bound tau. We identified 542 This included abundant detection many known be present such as tau, ubiquitin, neurofilament apolipoprotein E. Affinity confirmed 75 interacted PHF1-immunoreactive Twenty-nine have been previously associated therefore validating our proteomic approach. More importantly, 34 had total but not yet linked directly (e.g. protein VAMP2, vacuolar-ATPase subunit ATP6V0D1); therefore, provide new evidence they interact In addition, also 12 novel proteins, physiologically or pathologically RNA binding HNRNPA1). Network analysis showed interactome enriched involved ubiquitination pathway phagosome maturation. Importantly, were able pinpoint specific pathways for first time, providing potential pathogenic mechanisms can explored future studies. Combined, results reveal drug targets treatment tauopathies insight into how mediates its toxicity

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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Extracellular protein components of amyloid plaques and their roles in Alzheimer’s disease pathology

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Aug. 28, 2021

Abstract Alzheimer’s disease (AD) is pathologically defined by the presence of fibrillar amyloid β (Aβ) peptide in extracellular senile plaques and tau filaments intracellular neurofibrillary tangles. Extensive research has focused on understanding assembly mechanisms neurotoxic effects Aβ during last decades but still we only have a brief associated biological processes. This review highlights many other constituents that, beside Aβ, are accumulated plaques, with focus proteins. All living organisms rely delicate network protein functionality. Deposition significant amounts certain proteins insoluble inclusions will unquestionably lead to disturbances network, which may contribute AD copathology. paper provide comprehensive overview that been shown interact discussion their potential roles pathology. Methods can expand knowledge about how incorporated described. Top-down methods analyze post-mortem tissue bottom-up approaches molecular insights organization plaque-like particles compared. Finally, analysis Aβ-interacting partners enriched functional structural key words presented.

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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Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer’s disease

Neuron, Journal Year: 2022, Volume and Issue: 111(1), P. 15 - 29.e8

Published: Nov. 10, 2022

Language: Английский

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