Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

Cell, Journal Year: 2019, Volume and Issue: 179(2), P. 312 - 339

Published: Sept. 26, 2019

Language: Английский

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Formation of a protein corona on the surface of extracellular vesicles in blood plasma

Journal of Extracellular Vesicles, Journal Year: 2021, Volume and Issue: 10(11)

Published: Sept. 1, 2021

Abstract In this study we tested whether a protein corona is formed around extracellular vesicles (EVs) in blood plasma. We isolated medium‐sized nascent EVs of THP1 cells as well Optiprep‐purified platelets, and incubated them EV‐depleted plasma from healthy subjects patients with rheumatoid arthritis. were subjected to differential centrifugation, size exclusion chromatography, or density gradient ultracentrifugation followed by mass spectrometry. Plasma protein‐coated had higher compared the ones carried numerous newly associated proteins. Interactions between proteins confirmed confocal microscopy, capillary Western immunoassay, immune electron microscopy flow cytometry. identified nine shared EV (ApoA1, ApoB, ApoC3, ApoE, complement factors 3 4B, fibrinogen α‐chain, immunoglobulin heavy constant γ2 γ4 chains), which appear be common among EVs, viruses artificial nanoparticles An unexpected finding was high overlap composition aggregates. This explained our that besides diffuse, patchy corona, large aggregates also associate surface EVs. However, while an external cargo induced increased expression TNF‐α, IL‐6, CD83, CD86 HLA‐DR human monocyte‐derived dendritic cells, EV‐free no effect. conclusion, data may shed new light on origin commonly reported ‘contamination’ preparations add perspective research.

Language: Английский

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Herpes Simplex Virus-1 in the Brain: The Dark Side of a Sneaky Infection

Trends in Microbiology, Journal Year: 2020, Volume and Issue: 28(10), P. 808 - 820

Published: May 5, 2020

After primary infection, HSV-1 can reach the central nervous system where, in rare cases, it replicates and triggers an acute inflammatory response resulting herpes simplex encephalitis (HSE).The presence of genome has been revealed tissues peripheral individuals with no clinical signs HSE.In humans, levels circulating anti-HSV immunoglobulins, considered as markers reactivation, have positively correlated increased risk Alzheimer's disease (AD).Experimental data show that infection neurons activates neurotoxic pathways typical AD, repeated reactivations brain infected mice produce AD-like phenotype.Further studies are required to get greater mechanistic understanding causal links between recurrent infections AD well validate experimental findings humans. Herpes virus-1 (HSV-1) establishes latency preferentially sensory ganglia. A variety stresses induce virus, which spreads then actively site (usually lips or eyes). Viral particles produced following reactivation also brain, causing a but severe form diffuse namely encephalitis. Most time, this is clinically asymptomatic. However, was recently production accumulation neuropathological biomarkers disease. In review we discuss different cellular molecular mechanisms underlying long-term damage caused by brain. widely distributed neurotropic human pathogen transmitted mainly intimate contact susceptible individuals, causes labial, ocular, genital [1.Roizman B. et al.Herpes viruses.in: Knipe D.M. Fields Virology. 6th edn. Wolters Kluwer/Lippincott Williams & Wilkins, 2013: 1823-1897Google Scholar]. Primary usually occurs during childhood: over 60% under 50 years age worldwide [2.Looker K.J. al.Global regional estimates prevalent incident virus type 1 2012.PLoS One. 2015; 10e0140765Crossref PubMed Scopus (203) Google epithelial cells, becomes latent (PNS) be periodically reactivated subclinical episodes throughout life Although sympathetic affected, infects close [3.Bastian F.O. al.Herpesvirushominis: isolation from trigeminal ganglion.Science. 1972; 178: 306-307Crossref Scholar,4.Warren K.G. al.Isolation superior cervical vagus ganglions beings.N. Engl. J. Med. 1978; 298: 1068-1069Crossref Scholar], subsequently traveling retrogradely along axon cell body Studies animal models shown (CNS) [5.Kastrukoff L. al.Central immune inoculated into lip 1.J. Neuroimmunol. 1982; 2: 295-305Abstract Full Text PDF Scholar, 6.Rock D.L. Fraser N.W. Detection latently mice.Nature. 1983; 302: 523Crossref (226) 7.Shimeld C. al.Spread distribution after intraocular mouse.Arch. Virol. 1985; 85: 175-187Crossref (0) 8.Dyson H. within ocular nerves mouse: demonstration viral antigen whole mounts eye tissue.J. Gen. 1987; 68: 2989-2995Crossref 9.Mori I. al.The vomeronasal chemosensory route neuroinvasion virus.Virology. 2005; 334: 51-58Crossref 10.Chen S.H. al.Efficient mouse tissues.J. 2006; 80: 12387-12392Crossref (26) 11.Yao H.W. al.In vivo occur before occurring ganglion.J. 2014; 88: 11264-11270Crossref (28) 12.Jennische E. anterior commissure pathway for contralateral spread olfactory tract infection.J. Neurovirol. 21: 129-147Crossref (13) 13.Doll J.R. al.Infectious brainstem ganglia.J. 2019; 93: e02209-e02218Crossref (3) 14.De Chiara G. al.Recurrent induces hallmarks neurodegeneration cognitive deficits mice.PLoS Pathog. 15e1007617Crossref (12) Scholar] (Figures 2A ). replication may result (HSE) (reviewed [15.Gnann Jr., J.W. Whitley R.J. encephalitis: update.Curr. Infect. Dis. Rep. 2017; 19: 13Crossref (42) Scholar]) milder/asymptomatic eventually followed [16.Olsson al.HSV brains without dementia: TASTY series.Dis. Model. Mech. 2016; 9: 1349-1355Crossref growing evidence indicates cumulative effects 'mild' neuronal similar found neurodegenerative disorders such (AD), most common dementia elderly (Box 1) [17.De agents neurodegeneration.Mol. Neurobiol. 2012; 46: 614-638Crossref (69) Here, recent knowledge on pathogenic reactivations.Figure 2Schematic Representation Simplex Virus-1 Human Murine Brain Areas.Show full caption(A) Sagittal representation murine showing areas detected oral, nasal, inoculation (indicated colored dots) models; related studies, detection methods, listed below. (B) (left) external (right) DNA postmortem brains; methods Colored HSV-1-positive. (See Scholar,36.Fraser tissue.Proc. Natl. Acad. Sci. U. S. A. 1981; 78: 6461-6465Crossref Scholar,37.Baringer Pisani P. genomes tissue analyzed polymerase chain reaction.Ann. Neurol. 1994; 36: 823-829Crossref Scholar,68.Jamieson G.A. al.Latent normal brains.J. 1991; 33: 224-227Crossref Scholar,69.Ithzaki R.F. disease.Lancet. 1997; 349: 241-244Abstract (384) Scholar,105.Wozniak M.A. located amyloid plaques.J. Pathol. 2009; 217: 131-138Crossref (186) Scholar,115.Gordon al.Detection (types 2) herpesvirus 6 reaction.Clin. Diagn. 1996; 6: 33-40Abstract 116.Itabashi 1102Abstract 117.Cheon M.S. al.Evidence relation Down syndrome disease.Electrophoresis. 2001; 22: 445-448Crossref Scholar].)View Large Image Figure ViewerDownload Hi-res image Download (PPT)Box 1Alzheimer's DiseaseAlzheimer's (AD) estimated 40–50 million currently affected worldwide, number expected double next 20 [63.Scheltens al.Alzheimer's 388: 505-517Abstract (1214) characterized progressive impairment functions, particularly memory. While genetic mutations precursor protein (APP) presenilin proteins account small percentage cases [familial (FAD)], majority sporadic (SAD), thought involve as-yet-unidentified environmental factors. There effective therapy available pharmacological treatments primarily aimed at enhancing cholinergic activity, reduced patients, delaying formation plaques (see Box 3). Several mechanisms, including beta (Aβ) phospho Tau (pTau) oligomers, oxidative stress, mitochondrial dysfunction, neuroinflammation proposed contribute onset progression. Recent epidemiological strongly support hypothesis microbial factors AD. Specifically, type-1 gaining attention because its ability cause recurrent, life-long infection. (A) Scholar].) consists linear double-stranded icosapentahedral capsid. The capsid surrounded amorphous proteinaceous coating (the tegument) envelope, multiple glycoprotein spikes embedded. Virus binding entry host cells mediated specific association glycoproteins (gB, gC, gD, gH/gL complex) receptors target mediator (HVEM), heparan sulfate moieties, cell-adhesion nectin-1 nectin-2 [18.Hilterbrand A.T. Heldwein E.E. Go gadget glycoprotein! draws sizeable tool kit customize diverse routes.PLoS 15e1007660Crossref (1) Scholar]). enters fusion membranes, process interaction gD [19.Richart S.M. al.Entry vitro Nectin-1/HveC.J. 2003; 77: 3307-3311Crossref (63) This termini ganglia (TG) innervate orofacial corneal layer. capsids travel retrograde axonal transport, enter ganglion neurons, release nucleus establish favored inefficient transport tegument transactivator VP16, efficiently activate lytic program, described below [20.Sawtell N.M. Thompson R.L. De novo VP16 expression gates dynamic programmatic transition sets latent/lytic balance ganglia.PLoS 12e1005877Crossref [21.Wilson A.C. Mohr cultured affair: HSV neurons.Trends Microbiol. 20: 604-611Abstract (76) Latent persist episomal forms nucleus, where they interact promyelocytic leukemia (PML) nuclear bodies (NBs) involved establishment [22.Catez F. al.HSV-1 subnuclear positioning associations host-cell PML-NBs centromeres regulate LAT locus transcription neurons.PLoS 8e1002852Crossref 23.Maroui al.Latency determined environment.PLoS 12e1005834Crossref (18) 24.Cohen al.Promyelocytic latent/quiescent chromatinization through PML NB/histone H3.3/H3.3 chaperone axis.PLoS 2018; 14e1007313Crossref (7) During latency, chromatinized heterochromatic histone marks, whereby only subset genes expressed [25.Knipe Cliffe Chromatin control infection.Nat. Rev. 2008; 211-221Google Scholar,26.Bloom D.C. al.Epigenetic regulation gene expression.Biochim. Biophys. Acta. 2010; 1799: 246-256Crossref (130) abundant products latency-associated transcripts (LATs), 8.3/9 kb transcript two stable introns (2.0 1.5 kb) derived rapid splicing Scholar,25.Knipe addition LATs, produces several microRNAs (miRNA) Glossary) [27.Krause P.R. preliminary characterization 1988; 62: 4819-4823Crossref Scholar,28.Umbach J.L. al.MicroRNAs mRNAs.Nature. 454: 780-783Crossref (460) act synergistically LATs repress inhibition apoptosis stimulation [29.Cokarić Brdovčak M. deregulation micrornas.Noncoding RNA. 4: 36Google range stimuli, fever, emotional hormone imbalance, UV exposure, trauma, immunosuppression, reactivate These directly affect HSV-1-infected level surrounding, non-neuronal (e.g., satellite glia CD8+ T cells), promoting Newly synthesized sustain [30.Thompson al.De synthesis coordinates exit vivo.PLoS 5e1000352Crossref Reactivation results productive although abortive Scholar,31.Ma J.Z. al.Lytic frequent correlates engagement cell-intrinsic transcriptional response.PLoS 10e1004237Crossref begins sequential three subsets [immediate early (IE), (E), late (L) genes] RNA II. initial IE genes, E expression, turn L genes. Structural new assembled capsids, translocate cytoplasm, probably budding inner membrane (envelopment phase) fusing outer (de-envelopment phase). Naked acquire their definitive envelope (re-envelopment vesicles trans-Golgi network, mature virion exits near [32.Miranda-Saksena al.Infection neurons: role cytoskeleton.Viruses. 10: 92Crossref Alternatively, naked glycoproteins, complete virions, anterogradely inside separate anchored microtubule scaffolding, reaching shaft tip periphery, released Usually, gives rise blisters, sores, ulcers asymptomatic, despite shedding newly infectious [33.Ramchandani tears, nasal oral mucosa healthy adults.Sex. Transm. 43: 756Crossref Because pseudounipolar, CNS via anterograde transport. one branches TG projects nuclei brainstem, projections thalamus and, there, cortex. therefore direct [34.Bearer E.L. HSV, disease: relationships.Fut. 7: 885-899Crossref HSE, (estimated incidence: 2.5–12 cases/million/year [35.Modi al.Burden United States.J. 264: 1204-1208Crossref (17) 70% mortality untreated patients up 30% combined high incidence neurological sequelae treated antivirals. one-third two-thirds all HSE respectively suggesting [36.Fraser Postmortem must interpreted caution, confounding taken fixation/storage lateralization, handling, contamination, protein/nucleic acid degradation, impact antemortem drug duration agonal status (discussed [37.Baringer Scholar,38.Ferrer al.Effects formalin fixation, paraffin embedding, time storage preservation tissue: BrainNet Europe study.Brain 2007; 17: 297-303Crossref these unlikely influenc

Language: Английский

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The Biomolecular Corona of Lipid Nanoparticles for Gene Therapy

Bioconjugate Chemistry, Journal Year: 2020, Volume and Issue: 31(9), P. 2046 - 2059

Published: Aug. 7, 2020

Gene therapy holds great potential for treating almost any disease by gene silencing, protein expression, or correction. To efficiently deliver the nucleic acid payload to its target tissue, genetic material needs be combined with a delivery platform. Lipid nanoparticles (LNPs) have proven excellent vectors and are increasingly entering into routine clinical practice. Over past two decades, optimization of LNP formulations has led well-established body knowledge culminating in first-ever RNA interference therapeutic using technology, i.e., Onpattro, many more development various payloads. Screening lipid library vivo optimal silencing potency hepatocytes resulted identification Onpattro formulation. Subsequent studies discovered that key Onpattro's liver tropism is ability form specific "biomolecular corona". In fact, apolipoprotein E (ApoE), among other proteins, adsorbed surface enables hepatocyte targeting. This proof-of-principle example demonstrates use biomolecular corona targeting receptors cells, thereby opening up road rationally designing LNPs. date, however, only few explored detail LNPs, how modulate remains poorly understood. this review, we summarize recent discoveries about corona, expanding gained LNPs delivery. particular, address particle stability, biodistribution, can influenced biological environment. used as case study describe both successful an formulation influence Moreover, outline techniques available isolate analyze highlight their advantages drawbacks. Finally, discuss possible implications examine exploiting strategy beyond develop next-generation therapies.

Language: Английский

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The Microbiome as a Modifier of Neurodegenerative Disease Risk

Cell Host & Microbe, Journal Year: 2020, Volume and Issue: 28(2), P. 201 - 222

Published: Aug. 1, 2020

Language: Английский

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Mapping and identification of soft corona proteins at nanoparticles and their impact on cellular association

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Sept. 10, 2020

Abstract The current understanding of the biological identity that nanoparticles may acquire in a given milieu is mostly inferred from hard component protein corona (HC). composition soft (SC) proteins and their relevance have remained elusive due to lack analytical separation methods. Here, we identify set specific with weak interactions at silica polystyrene by using an situ click-chemistry reaction. We show these SC are present also HC, but specifically enriched after capture, suggesting main distinction between HC differential binding strength same proteins. Interestingly, weakly interacting revealed as modulators nanoparticle-cell association mainly through dynamic nature. therefore highlight should be considered when evaluating nano-bio interfaces.

Language: Английский

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COVID-19 and possible links with Parkinson’s disease and parkinsonism: from bench to bedside

npj Parkinson s Disease, Journal Year: 2020, Volume and Issue: 6(1)

Published: Aug. 20, 2020

Abstract This Viewpoint discusses insights from basic science and clinical perspectives on coronavirus disease 2019 (COVID-19)/severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection in the brain, with a particular focus Parkinson’s disease. Major points include that neuropathology studies have not answered central issue of whether virus enters nervous system neurons, astrocytes or microglia, brain vascular cell types express yet been identified. Currently, there is no clear evidence for human neuronal astrocyte expression angiotensin-converting enzyme 2 (ACE2), major receptor viral entry, but ACE2 may be activated by inflammation, comparison healthy infected brains important. In contrast to 1918 influenza pandemic avian flu, reports encephalopathy COVID-19 slow emerge, are so far documented parkinsonism apart single case report. We recommend consensus guidelines treatment patients COVID-19. While role causing exacerbating appears unlikely at this time, aggravation specific motor non-motor symptoms has reported, it will important monitor subjects after recovery, particularly those persisting hyposmia.

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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SARS-CoV-2 spike protein interactions with amyloidogenic proteins: Potential clues to neurodegeneration

Biochemical and Biophysical Research Communications, Journal Year: 2021, Volume and Issue: 554, P. 94 - 98

Published: March 24, 2021

Language: Английский

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Mechanisms and pathology of protein misfolding and aggregation

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(12), P. 912 - 933

Published: Sept. 8, 2023

Language: Английский

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