title: Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits.
abstract: Alzheimer's disease (AD) is characterized by the presence of parenchymal amyloid-β (Aβ) plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles. Currently there are no effective treatments for AD. Immunotherapeutic approaches under development are hampered by complications related to ineffectual clearance of CAA. Genome-wide association studies have demonstrated the importance of microglia in AD pathogenesis. Microglia are the primary innate immune cells of the brain. Depending on their activation state and environment, microglia can be beneficial or detrimental. In our prior work, we showed that stimulation of innate immunity with Toll-like receptor 9 agonist, class B CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs), can reduce amyloid and tau pathologies without causing toxicity in Tg2576 and 3xTg-AD mouse models. However, these transgenic mice have relatively little CAA. In the current study, we evaluated the therapeutic profile of CpG ODN in a triple transgenic mouse model, Tg-SwDI, with abundant vascular amyloid, in association with low levels of parenchymal amyloid deposits. Peripheral administration of CpG ODN, both before and after the development of CAA, negated short-term memory deficits, as assessed by object-recognition tests, and was effective at improving spatial and working memory evaluated using a radial arm maze. These findings were associated with significant reductions of CAA pathology lacking adverse effects. Together, our extensive evidence suggests that this innovative immunomodulation may be a safe approach to ameliorate all hallmarks of AD pathology, supporting the potential clinical applicability of CpG ODN.
  
  
  
  Recent genetic studies have underscored the emerging role of microglia in Alzheimer's disease (AD) pathogenesis. Microglia lose their amyloid-β-clearing capabilities with age and as AD progresses. Therefore, the ability to modulate microglia profiles offers a promising therapeutic avenue for reducing AD pathology. Current immunotherapeutic approaches have been limited by poor clearance of a core AD lesion, cerebral amyloid angiopathy (CAA). The present study used Tg-SwDI mice, which have extensive CAA. We found that stimulation of the innate immune system and microglia/macrophage activation via Toll-like receptor 9 using CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs) leads to cognitive improvements and CAA reduction, without associated toxicity. Our data indicate that this novel concept of immunomodulation represents a safer method to reduce all aspects of AD pathology and provide essential information for potential clinical use of CpG ODN.
authors.affiliation: Center for Cognitive Neurology.|Department of Neurology.
authors.forename: Henrieta
authors.identifier: 0000-0003-0766-9463
authors.initials: H
authors.lastname: Scholtzova
authors.affiliation: Center for Cognitive Neurology.
authors.forename: Eileen
authors.identifier: 0000-0001-9631-9101
authors.initials: E
authors.lastname: Do
authors.affiliation: Center for Cognitive Neurology.|Department of Neurology.
authors.forename: Shleshma
authors.identifier: 0000-0003-4228-1499
authors.initials: S
authors.lastname: Dhakal
authors.affiliation: Center for Cognitive Neurology.|Department of Neurology.
authors.forename: Yanjie
authors.identifier: 0000-0001-9382-4401
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Center for Cognitive Neurology.|Department of Neurology.
authors.forename: Shan
authors.identifier: 0000-0002-6935-2894
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Immunology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314.
authors.forename: Pankaj D
authors.initials: PD
authors.lastname: Mehta
authors.affiliation: Center for Cognitive Neurology, thomas.wisniewski@nyumc.org.|Department of Neurology.|Department of Pathology, and.|Department of Psychiatry, New York University School of Medicine, New York, New York 10016, and.
authors.forename: Thomas
authors.identifier: 0000-0002-3379-8966
authors.initials: T
authors.lastname: Wisniewski
mesh_terms: D000818:Animals; D016657:Cerebral Amyloid Angiopathy / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology / Q000627:therapeutic use; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology* / Q000378:metabolism*
chemical_list: C423449:CpG ODN 1826; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9
keywords: Alzheimer's disease; Toll-like receptor 9; amyloid β; immunomodulation; innate immunity; transgenic mice