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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Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease

Science Translational Medicine, Journal Year: 2016, Volume and Issue: 8(340)

Published: May 25, 2016

β-Amyloid protein oligomerization and fibrillization, known to be pathogenic in Alzheimer’s disease, may play a physiological role microbial entrapment innate immunity.

Language: Английский

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Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection

Neuron, Journal Year: 2018, Volume and Issue: 99(1), P. 56 - 63.e3

Published: July 1, 2018

Language: Английский

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Microbes and Alzheimer’s Disease

Journal of Alzheimer s Disease, Journal Year: 2016, Volume and Issue: 51(4), P. 979 - 984

Published: April 12, 2016

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, we write to express our concern that one particular aspect of the has been neglected, even thoug ...

Language: Английский

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Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: June 30, 2023

Abstract Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as molecular driver pathogenesis progression. Aβ prime target for development AD therapy. However, repeated failures Aβ-targeted clinical trials have cast considerable doubt on amyloid cascade hypothesis whether drug followed correct course. recent successes targeted assuaged those doubts. In this review, we discussed evolution over last 30 years summarized application diagnosis modification. particular, extensively pitfalls, promises important unanswered questions regarding current anti-Aβ therapy, well strategies further study more feasible approaches optimization prevention treatment.

Language: Английский

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The antimicrobial protection hypothesis of Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2018, Volume and Issue: 14(12), P. 1602 - 1614

Published: Oct. 9, 2018

Abstract Objective We explore here a novel model for amyloidogenesis in Alzheimer's disease (AD). This new perspective on AD amyloidosis seeks to provide rational framework incorporating recent and seemingly independent findings the antimicrobial role of β‐amyloid emerging experimental, genetic, epidemiological data, suggesting innate immune‐mediated inflammation propagates neurodegeneration. Background pathology is characterized by cerebral deposition amyloid‐β protein (Aβ) as β‐amyloid. Genetic studies have confirmed key Aβ AD, revealing that mutation‐mediated shifts peptides generation lead early onset familial disease. However, appears normal majority patients, who lack mutations. In prevailing models nonfamilial individual genetics age‐associated changes brain milieu promote an intrinsically abnormal propensity self‐association. are increasingly inconsistent with characterization oligomerization nonphysiological exclusively pathological activity. Recent suggest ancient, highly conserved effector molecule immunity. Moreover, appear be important immune pathways mediate pathogen entrapment protect against infection. New inflammation‐mediated neurodegeneration immunity led emergence “Antimicrobial Protection Hypothesis” AD. this model, response genuine, or mistakenly perceived, immunochallenge. first entraps neutralizes invading pathogens fibrillization drives neuroinflammatory help fight infection clear β‐amyloid/pathogen deposits. chronic activation pathway leads sustained Mounting data link elevated microbe levels The Antimicrobial Hypothesis reveals how increased microbial burden may directly exacerbate deposition, inflammation, progression. Amyloid cascade hypothesis protection modality Aβ's pathophysiology shifted from stochastic behavior toward dysregulated response. still Thus, extends but remains broadly consistent Cascade overwhelming showing primacy pathology.

Language: Английский

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Self-assembling dipeptide antibacterial nanostructures with membrane disrupting activity

Nature Communications, Journal Year: 2017, Volume and Issue: 8(1)

Published: Nov. 3, 2017

Abstract Peptide-based supramolecular assemblies are a promising class of nanomaterials with important biomedical applications, specifically in drug delivery and tissue regeneration. However, the intrinsic antibacterial capabilities these have been largely overlooked. The recent identification common characteristics shared by self-assembling peptides provides paradigm shift towards development agents. Here we present activity self-assembled diphenylalanine, which emerges as minimal model for polymers. diphenylalanine nano-assemblies completely inhibit bacterial growth, trigger upregulation stress-response regulons, induce substantial disruption to morphology, cause membrane permeation depolarization. We demonstrate specificity interactions materials integration peptide into scaffolds. This study insights significance interplay between self-assembly antimicrobial establishes innovative design principles toward agents materials.

Language: Английский

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The role of astrocytes in amyloid production and Alzheimer's disease

Open Biology, Journal Year: 2017, Volume and Issue: 7(12), P. 170228 - 170228

Published: Dec. 1, 2017

Alzheimer's disease (AD) is marked by the presence of extracellular amyloid beta (Aβ) plaques, intracellular neurofibrillary tangles (NFTs) and gliosis, activated glial cells, in brain. It thought that Aβ plaques trigger NFT formation, neuronal cell death, neuroinflammation gliosis and, ultimately, cognitive impairment. There are increased numbers reactive astrocytes AD, which surround secrete proinflammatory factors can phagocytize break down Aβ. was cells were major source However, mounting evidence suggests may play an additional role AD secreting significant quantities contributing to overall burden Astrocytes most numerous type brain, therefore even minor secretion from individual could prove be substantial when taken across whole Reactive have levels three necessary components for production: precursor protein, β-secretase (BACE1) γ-secretase. The identification environmental factors, such as neuroinflammation, promote astrocytic production, redefine how we think about developing therapeutics AD.

Language: Английский

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The Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease

Frontiers in Aging Neuroscience, Journal Year: 2018, Volume and Issue: 10

Published: April 25, 2018

Amyloid-ß (Aß) is best known as the misfolded peptide that involved in pathogenesis of Alzheimer's disease (AD), and it currently primary therapeutic target attempts to arrest course this disease. This notoriety has overshadowed evidence Aß serves several important physiological functions. present throughout lifespan, been found all vertebrates examined thus far, its molecular sequence shows a high degree conservation. These features are typical factor contributes significantly biological fitness, suggestion supported by functions beneficial for brain. The putative roles include protecting body from infections, repairing leaks blood-brain barrier, promoting recovery injury, regulating synaptic function. Evidence these comes vitro vivo studies, which have shown cellular production rapidly increases response challenge often diminishes upon recovery. further adverse outcomes clinical trials attempted deplete order treat AD. We suggest anti-Aß therapies will produce fewer effects if triggers deposition (e.g. pathogens, hypertension diabetes) addressed first.

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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