title: Reductions in amyloid-beta-derived neuroinflammation, with minocycline, restore cognition but do not significantly affect tau hyperphosphorylation.
abstract: Cognitive decline in Alzheimer's disease (AD) occurs as a result of the buildup of pathological proteins and downstream events including an elevated and altered inflammatory response. Inflammation has previously been linked to increased abnormal phosphorylation of tau protein. To determine if endogenous amyloid-beta (Abeta)-induced neuroinflammation drives tau phosphorylation in vivo, we treated 8-month-old 3xTg-AD with minocycline, an anti-inflammatory agent, to assess how it influenced cognitive decline and development of pathology. 4 months of treatment restored cognition to non-transgenic performance. Inflammatory profiling revealed a marked decrease in GFAP, TNFalpha, and IL6 and an increase in the CXCL1 chemokines KC and MIP1a. Minocycline also reduced levels of insoluble Abeta and soluble fibrils. Despite reducing levels of the tau kinase cdk5 coactivator p25, minocycline did not have wide effects on tau pathology with only one phospho-epitope showing reduction with treatment (S212/S214). The sum of these findings shows that reduction of the inflammatory events in an AD mouse model prevents cognitive deficits associated with pathology, but that endogenous Abeta-derived neuroinflammation does not contribute significantly to the development of tau pathology.
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697-4545, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Parachikova
authors.forename: Vitaly
authors.initials: V
authors.lastname: Vasilevko
authors.forename: David H
authors.initials: DH
authors.lastname: Cribbs
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008911:Minocycline / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D021641:Recognition, Psychology / Q000187:drug effects; D024801:Tauopathies / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000900:Anti-Bacterial Agents; D016875:tau Proteins; D008911:Minocycline