دورية أكاديمية
أعرض في EDS

Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites

التفاصيل البيبلوغرافية
العنوان: Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites
المؤلفون: Felix S. Meier‐Stephenson, Vanessa C. Meier‐Stephenson, Michael D. Carter, Autumn R. Meek, Yanfei Wang, Luzhe Pan, Qiangwei Chen, Sheila Jacobo, Fan Wu, Erhu Lu, Gordon A. Simms, Laural Fisher, Alaina J. McGrath, Virgil Fermo, Christopher J. Barden, Harman D.S. Clair, Todd N. Galloway, Arun Yadav, Valérie Campágna‐Slater, Mark Hadden, Mark Reed, Marcia Taylor, Brendan Kelly, Elena Diez‐Cecilia, Igri Kolaj, Clarissa Santos, Imindu Liyanage, Braden Sweeting, Paul Stafford, Robert Boudreau, G. Andrew Reid, Ryan S. Noyce, Leanne Stevens, Agnieszka Staniszewski, Hong Zhang, Mamidanna R. V. S. Murty, Pascale Lemaire, Solenne Chardonnet, Christopher D. Richardson, Valérie Gabelica, Edwin DePauw, Richard Brown, Sultan Darvesh, Ottavio Arancio, Donald F. Weaver
المصدر: Alzheimer’s & Dementia: Translational Research & Clinical Interventions, Vol 8, Iss 1, Pp n/a-n/a (2022)
بيانات النشر: Wiley, 2022.
سنة النشر: 2022
المجموعة: LCC:Neurology. Diseases of the nervous system
LCC:Geriatrics
مصطلحات موضوعية: Alzheimer's disease, amyloid beta, antimicrobial peptide, arginine, autoimmune, cytokine, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
الوصف: Abstract Introduction Alzheimer's disease (AD) is characterized by neurotoxic immuno‐inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aβ) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic–molecular mechanisms of cytokine‐mediated and Aβ‐mediated neurotoxicities in AD. Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small‐molecule therapeutics for AD. Results In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon “self” neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane‐penetrating attack by antimicrobial peptides (AMPs) such as Aβ. After this self‐attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self‐perpetuating autoimmune cycle. AD thus emerges as a brain‐centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti‐AD molecules capable of chemical modification into multi‐site therapeutic modulators targeting AD's complex immunopathic–proteopathic pathogenesis. Discussion Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug‐like analogues of these endogenous regulators represents a novel therapeutic approach for AD.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2352-8737
Relation: https://doaj.org/toc/2352-8737
DOI: 10.1002/trc2.12283
URL الوصول: https://doaj.org/article/1e2d8b504a1f482e94ad2f6036b37c9c
رقم الأكسشن: edsdoj.1e2d8b504a1f482e94ad2f6036b37c9c
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:23528737
DOI:10.1002/trc2.12283