Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease
Deepak Kumar,Se Hoon Choi,Kevin J. Washicosky,William A. Eimer,Stephanie Tucker,Jessica Ghofrani,Aaron Lefkowitz,Gawain McColl,Lee E. Goldstein,Rudolph E. Tanzi,Robert D. Moir +10 more
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TLDR
In vivo data showing that Aβ expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD are presented, and Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide are shown.Abstract:
The amyloid-β peptide (Aβ) is a key protein in Alzheimer’s disease (AD) pathology. We previously reported in vitro evidence suggesting that Aβ is an antimicrobial peptide. We present in vivo data showing that Aβ expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD. We show that Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide. Collectively, our data are consistent with a model in which soluble Aβ oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating β-amyloid fibrils mediate agglutination and eventual entrapment of unatttached microbes. Consistent with our model, Salmonella Typhimurium bacterial infection of the brains of transgenic 5XFAD mice resulted in rapid seeding and accelerated β-amyloid deposition, which closely colocalized with the invading bacteria. Our findings raise the intriguing possibility that β-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for Aβ, as has been described for other antimicrobial peptides.read more
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Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease
Timothy R. Sampson,Justine W. Debelius,Taren Thron,Stefan Janssen,Gauri G. Shastri,Zehra Esra Ilhan,Collin Challis,Catherine E. Schretter,Sandra Rocha,Viviana Gradinaru,Marie-Françoise Chesselet,Ali Keshavarzian,Kathleen M. Shannon,Rosa Krajmalnik-Brown,Pernilla Wittung-Stafshede,Rob Knight,Sarkis K. Mazmanian +16 more
TL;DR: It is reported herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology, and suggested that alterations in the human microbiome represent a risk factor for PD.
Journal ArticleDOI
The Microbiota-Gut-Brain Axis
John F. Cryan,Kenneth J. O’Riordan,Caitlin S. M. Cowan,Kiran V. Sandhu,Thomaz F.S. Bastiaanssen,Marcus Boehme,Martín Gabriel Codagnone,Sofia Cussotto,Christine Fülling,Anna V. Golubeva,Katherine E. Guzzetta,Minal Jaggar,Caitriona M. Long-Smith,Joshua M. Lyte,Jason A. Martin,Alicia Molinero-Perez,Gerard M. Moloney,Emanuela Morelli,Enrique Morillas,Rory C. O'Connor,Joana S Cruz-Pereira,Veronica L. Peterson,Kieran Rea,Nathaniel L. Ritz,Eoin Sherwin,Simon Spichak,Emily M. Teichman,Marcel van de Wouw,Ana Paula Ventura-Silva,Shauna E. Wallace-Fitzsimons,Niall P. Hyland,Gerard Clarke,Timothy G. Dinan +32 more
TL;DR: Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
Journal ArticleDOI
Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders
TL;DR: This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy.
Journal ArticleDOI
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.
Justin M. Long,David M. Holtzman +1 more
TL;DR: Recent advances in the understanding of AD pathobiology are reviewed and current treatment strategies are discussed, highlighting recent clinical trials and opportunities for developing future disease-modifying therapies.
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How neuroinflammation contributes to neurodegeneration.
TL;DR: Observations indicate that therapies targeting glial cells might provide benefit for those afflicted by neurodegenerative disorders, because the environment is affected during disease in a cascade of processes collectively termed neuroinflammation.
References
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Journal ArticleDOI
Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins
Mary P. Lambert,A. K. Barlow,Brett A. Chromy,C. Edwards,R. Freed,M. Liosatos,Todd E. Morgan,Irina Rozovsky,Barbara L. Trommer,Kirsten L. Viola,Pat Wals,Chuan Zhang,Caleb E. Finch,Grant A. Krafft,William L. Klein +14 more
TL;DR: It is hypothesized that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Abeta-derived diffusible ligands acting upon particular neural signal transduction pathways.
Journal ArticleDOI
Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation.
Holly Oakley,Sarah L. Cole,Sreemathi Logan,Erika Maus,Pei Shao,Jeffery Craft,Angela L. Guillozet-Bongaarts,Masuo Ohno,John F. Disterhoft,Linda J. Van Eldik,Robert W. Berry,Robert Vassar +11 more
TL;DR: 5XFAD mice rapidly recapitulate major features of AD amyloid pathology and may be useful models of intraneuronal Aβ42-induced neurodegeneration and amyloids plaque formation.
Journal ArticleDOI
Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective.
Rudolph E. Tanzi,Lars Bertram +1 more
TL;DR: The amyloid hypothesis based on both known and putative Alzheimer's disease genes is assessed, with positive results for beta-amyloid inaques andaques is confirmed in animals and humans.
Journal ArticleDOI
The Systemic Amyloidoses
TL;DR: Amyloidosis is not a single disease but a term for diseases that share a common feature: the extracellular deposition of pathologic insoluble fibrillar proteins in organs and tissues.
Journal ArticleDOI
The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide
Stephanie J. Soscia,James E. Kirby,Kevin J. Washicosky,Stephanie Tucker,Martin Ingelsson,Bradley T. Hyman,Mark Burton,Lee E. Goldstein,Scott Duong,Rudolph E. Tanzi,Robert D. Moir +10 more
TL;DR: The findings suggest Aβ is a hitherto unrecognized AMP that may normally function in the innate immune system and stands in stark contrast to current models of Aβ-mediated pathology and has important implications for ongoing and future AD treatment strategies.
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