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Acta Neuropathol Commun. 2016 Jun 23;4(1):63. doi: 10.1186/s40478-016-0336-1.

Increased tauopathy drives microglia-mediated clearance of beta-amyloid.

Author information

1
Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.
2
Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.
3
Institute for Memory Impairments and Neurological Disorders, University of California Irvine, 845 Health Science Rd, 3200 Gross Hall, Irvine, CA, 92697, USA.
4
Present Address: Department of Immunology, University of Connecticut School of Medicine, Farmington, CT, 06030, USA.
5
University Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer & Tauopathies, Lille, France.
6
Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA. mblurton@uci.edu.
7
Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA. mblurton@uci.edu.
8
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.

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.

KEYWORDS:

Amyloid; Aβ; Cytokines; Mice; Microglia; Pathology; Phagocytosis; Tau

PMID:
27339073
PMCID:
PMC4918195
DOI:
10.1186/s40478-016-0336-1
[Indexed for MEDLINE]
Free PMC Article

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