title: Increased tauopathy drives microglia-mediated clearance of beta-amyloid.
abstract: Alzheimer disease is characterized by the accumulation of β-amyloid (Aβ) plaques and tau-laden neurofibrillary tangles. Emerging studies suggest that in neurodegenerative diseases, aggregation of one protein species can promote other proteinopathies and that inflammation plays an important role in this process. To study the interplay between Aβ deposition, tau pathology, and microgliosis, we established a new AD transgenic mouse model by crossing 5xfAD mice with Thy-Tau22 transgenic mice. The resulting 'T5x' mice exhibit a greater than three-fold increase in misfolded and hyperphosphorylated tau and further substantiates the hypothesis that Aβ accelerates tau pathology. Surprisingly, T5x mice exhibit a 40-50 % reduction in Aβ plaque load and insoluble Aβ species when compared with aged-matched 5xfAD littermates. T5x mice exhibit significant changes in cytokine production, an almost doubling of microglial number, and a dramatic shift in microglia activation state. Furthermore, T5x microglia exhibit increased phagocytic capacity that enhances the clearance of insoluble Aβ and decreasing plaque load. Therefore, our results suggest that strategies to increase the phagocytic ability of microglia can be employed to reduce Aβ and that tau-induced changes in microglial activation state can promote the clearance of Aβ.
authors.affiliation: Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.|Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.
authors.forename: Wesley
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.|Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.
authors.forename: Edsel A
authors.initials: EA
authors.lastname: Abud
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California Irvine, 845 Health Science Rd, 3200 Gross Hall, Irvine, CA, 92697, USA.|Present Address: Department of Immunology, University of Connecticut School of Medicine, Farmington, CT, 06030, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Yeung
authors.affiliation: Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.|Institute for Memory Impairments and Neurological Disorders, University of California Irvine, 845 Health Science Rd, 3200 Gross Hall, Irvine, CA, 92697, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Lakatos
authors.affiliation: Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Nassi
authors.affiliation: Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Wang
authors.affiliation: University Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer & Tauopathies, Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Blum
authors.affiliation: University Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer & Tauopathies, Lille, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California Irvine, 845 Health Science Rd, 3200 Gross Hall, Irvine, CA, 92697, USA.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.affiliation: Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA. mblurton@uci.edu.|Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA. mblurton@uci.edu.|Institute for Memory Impairments and Neurological Disorders, University of California Irvine, 845 Health Science Rd, 3200 Gross Hall, Irvine, CA, 92697, USA. mblurton@uci.edu.
authors.forename: Mathew
authors.identifier: 0000-0002-7770-7157
authors.initials: M
authors.lastname: Blurton-Jones
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000502:physiology; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; C054369:MAPT protein, human; D016875:tau Proteins
keywords: Amyloid; Aβ; Cytokines; Mice; Microglia; Pathology; Phagocytosis; Tau