Mag-Net: Rapid enrichment of membrane-bound particles enables high coverage quantitative analysis of the plasma proteome DOI Creative Commons
Christine Wu, Kristine A. Tsantilas,

Jea Park

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 10, 2023

ABSTRACT Membrane-bound particles in plasma are composed of exosomes, microvesicles, and apoptotic bodies represent ∼1-2% the total protein composition. Proteomic interrogation this subset proteins augments representation tissue-specific proteins, representing a “liquid biopsy,” while enabling detection that would otherwise be beyond dynamic range liquid chromatography-tandem mass spectrometry unfractionated plasma. We have developed an enrichment strategy (Mag-Net) using hyper-porous strong-anion exchange magnetic microparticles to sieve membrane-bound from The Mag-Net method is robust, reproducible, inexpensive, requires <100 μL input. Coupled quantitative data-independent analytical strategy, we demonstrate can collect results for >37,000 peptides >4,000 with high precision. Using pipeline on small cohort patients neurodegenerative disease healthy age-matched controls, discovered 204 differentiate (q-value < 0.05) Alzheimer’s dementia (ADD) those without ADD. Our also 310 were different between Parkinson’s either ADD or cognitively normal individuals. machine learning able distinguish not mean ROC AUC = 0.98 ± 0.06.

Language: Английский

Microglia Phenotypes in Aging and Neurodegenerative Diseases DOI Creative Commons
Menbere Wendimu, Shelley B. Hooks

Cells, Journal Year: 2022, Volume and Issue: 11(13), P. 2091 - 2091

Published: June 30, 2022

Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays fundamental role in mediating the onset progression disease. Microglia, which function as first-line immune guardians central nervous system (CNS), are drivers neuroinflammation. Numerous human postmortem studies vivo imaging analyses have shown chronically activated microglia patients with various acute chronic neuropathological diseases. While microglial activation common feature NDs, exact pathological states complex often contradictory. However, there consensus that play biphasic conditions, detrimental protective phenotypes, overall response different phenotypes depends on nature duration inflammatory insult, well stage disease development. This review provides comprehensive overview current research responses health, aging, special emphasis heterogeneous phenotypic such hemorrhagic stroke (HS), Alzheimer's (AD), Parkinson's (PD). The primary focus translational preclinical animal models bulk/single-cell transcriptome samples. Additionally, this covers key receptors signaling pathways potential therapeutic targets to regulate during aging NDs. age-, sex-, species-specific differences will be briefly reviewed.

Language: Английский

Citations

186
Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy DOI Creative Commons
Lulu Jiang, Weiwei Lin, Cheng Zhang

et al.

Molecular Cell, Journal Year: 2021, Volume and Issue: 81(20), P. 4209 - 4227.e12

Published: Aug. 27, 2021

Language: Английский

Citations

128
Exosomes based strategies for brain drug delivery DOI
Fawad Ur Rehman, Yang Liu, Meng Zheng

et al.

Biomaterials, Journal Year: 2022, Volume and Issue: 293, P. 121949 - 121949

Published: Dec. 8, 2022

Language: Английский

Citations

114
In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo DOI
Abi G. Yates, Ryan Pink,

Uta Erdbrügger

et al.

Journal of Extracellular Vesicles, Journal Year: 2022, Volume and Issue: 11(1)

Published: Jan. 1, 2022

Abstract It is clear from Part I of this series that extracellular vesicles (EVs) play a critical role in maintaining the homeostasis most, if not all, normal physiological systems. However, majority our knowledge about EV signalling has come studying them disease. Indeed, EVs have consistently been associated with propagating disease pathophysiology. The analysis biofluids, obtained clinic, an essential work to improve understanding their interfere for therapeutic gain, more fundamental mechanisms by which they contribute pathogenic processes required. Only discovering how populations different biofluids change—size, number, and physicochemical composition—in clinical samples, may we then begin unravel functional roles translational models vitro vivo, can feedback clinic. In II review series, pathology will be discussed, focus on vivo evidence potential used as both biomarkers points intervention.

Language: Английский

Citations

109
Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired DOI Creative Commons
Wenjing Liang, Shakti Sagar, Rishith Ravindran

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 18, 2023

Abstract Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible generating most of the energy needed to sustain contraction. Dysfunctional mitochondria normally degraded via intracellular degradation pathways that converge on lysosome. Here, we identified an alternative mechanism eliminate when lysosomal function compromised. We show inhibition leads increased secretion in large extracellular vesicles (EVs). The EVs produced multivesicular bodies, and their release independent autophagy. Deletion small GTPase Rab7 cells or adult mouse heart containing ubiquitinated cargos, including intact mitochondria. secreted captured by macrophages without activating inflammation. Hearts from aged mice Danon disease patients have levels indicating activation vesicular during pathophysiology. Overall, findings establish eliminated through endosomal pathway inhibited.

Language: Английский

Citations

105
Synaptic oligomeric tau in Alzheimer’s disease — A potential culprit in the spread of tau pathology through the brain DOI Creative Commons
Martí Colom‐Cadena, C. T. M. Davies, Sònia Sirisi

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(14), P. 2170 - 2183.e6

Published: May 15, 2023

In Alzheimer's disease, fibrillar tau pathology accumulates and spreads through the brain synapses are lost. Evidence from mouse models indicates that trans-synaptically pre- to postsynapses oligomeric is synaptotoxic, but data on synaptic in human scarce. Here we used sub-diffraction-limit microscopy study accumulation postmortem temporal occipital cortices of control donors. Oligomeric present postsynaptic terminals, even areas without abundant deposition. Furthermore, there a higher proportion compared with phosphorylated or misfolded found at terminals. These suggest an early event pathogenesis may progress via trans-synaptic spread disease. Thus, specifically reducing be promising therapeutic strategy for

Language: Английский

Citations

99
Isolation of mitochondria-derived mitovesicles and subpopulations of microvesicles and exosomes from brain tissues DOI
Pasquale D’Acunzo, Yohan Kim, Jonathan M. Ungania

et al.

Nature Protocols, Journal Year: 2022, Volume and Issue: 17(11), P. 2517 - 2549

Published: Aug. 12, 2022

Language: Английский

Citations

87
Chronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading DOI Creative Commons
Nimansha Jain, Caroline A. Lewis, Jason D. Ulrich

et al.

The Journal of Experimental Medicine, Journal Year: 2022, Volume and Issue: 220(1)

Published: Sept. 9, 2022

Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene are associated with increased risk for late-onset AD. Genetic loss of or decreased TREM2 function impairs microglial response to amyloid-β (Aβ) plaques, resulting more diffuse Aβ plaques and peri-plaque neuritic dystrophy AD-tau seeding. Thus, microglia at a critical intersection tau pathologies Since genetically decreasing increases Aβ-induced seeding, we hypothesized that chronically increasing signaling would decrease amyloid-induced tau-seeding spreading. Using mouse model amyloidosis which is injected into brain induce Aβ-dependent seeding/spreading, found chronic administration an activating antibody activation but surprisingly NP-tau pathology dystrophy, without altering plaque burden. Our data suggest sustained through does not result strong amyloid removal may exacerbate pathology, have important clinical implications.

Language: Английский

Citations

86
Involvement of Astrocytes in the Formation, Maintenance, and Function of the Blood–Brain Barrier DOI Creative Commons
Gabriella Schiera, Carlo Maria Di Liegro,

Giuseppe Schirò

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(2), P. 150 - 150

Published: Jan. 12, 2024

The blood-brain barrier (BBB) is a fundamental structure that protects the composition of brain by determining which ions, metabolites, and nutrients are allowed to enter from blood or leave it towards circulation. BBB structurally composed layer capillary endothelial cells (BCECs) bound each other through tight junctions (TJs). However, its development as well maintenance properties controlled contact BCECs: pericytes, glial cells, even neurons themselves. Astrocytes seem, in particular, have very important role controlling most BBB. Here, we will focus on these latter since comprehension their roles physiology has been continuously expanding, including ability participate neurotransmission complex functions such learning memory. Accordingly, pathological conditions alter astrocytic can BBB's integrity, thus compromising many activities. In this review, also refer different kinds vitro models used study properties, evidencing modifications under conditions.

Language: Английский

Citations

37
Cellular and pathological functions of tau DOI
C Bravo, Sarah Naguib, Li Gan

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(11), P. 845 - 864

Published: July 16, 2024

Language: Английский

Citations

34