title: Amyloid β and Tau Alzheimer's disease related pathology is reduced by Toll-like receptor 9 stimulation.
abstract: Alzheimer's disease (AD) is the most common cause of dementia, and currently, there is no effective treatment. The major neuropathological lesions in AD are accumulation of amyloid β (Aβ) as amyloid plaques and congophilic amyloid angiopathy, as well as aggregated tau in the form of neurofibrillary tangles (NFTs). In addition, inflammation and microglia/macrophage function play an important role in AD pathogenesis. We have hypothesized that stimulation of the innate immune system via Toll-like receptor 9 (TLR9) agonists, such as type B CpG oligodeoxynucleotides (ODNs), might be an effective way to ameliorate AD related pathology. We have previously shown in the Tg2576 AD model that CpG ODN can reduce amyloid deposition and prevent cognitive deficits. In the present study, we used the 3xTg-AD mice with both Aβ and tau related pathology. The mice were divided into 2 groups treated from 7 to 20 months of age, prior to onset of pathology and from 11 to 18 months of age, when pathology is already present. We demonstrated that immunomodulatory treatment with CpG ODN reduces both Aβ and tau pathologies, as well as levels of toxic oligomers, in the absence of any apparent inflammatory toxicity, in both animal groups. This pathology reduction is associated with a cognitive rescue in the 3xTg-AD mice. Our data indicate that modulation of microglial function via TLR9 stimulation is effective at ameliorating all the cardinal AD related pathologies in an AD mouse model suggesting such an approach would have a greater chance of achieving clinical efficacy.
authors.forename: Henrieta
authors.initials: H
authors.lastname: Scholtzova
authors.forename: Peter
authors.initials: P
authors.lastname: Chianchiano
authors.forename: Jason
authors.initials: J
authors.lastname: Pan
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Sun
authors.forename: Fernando
authors.initials: F
authors.lastname: Goñi
authors.forename: Pankaj D
authors.initials: PD
authors.lastname: Mehta
authors.affiliation: Departments of Neurology, Pathology and Psychiatry, New York University School of Medicine, Rm 802, Alexandria ERSP, 450 East 29th Street, New York 10016, NY, USA. thomas.wisniewski@nyumc.org.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010766:Phosphorylation; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; C558298:Mapt protein, mouse; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D016875:tau Proteins