Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events

Kiran Bhaskar; Nicole Maphis; Guixiang Xu; Nicholas H. Varvel; Olga N. Kokiko-Cochran; Jason P. Weick; Susan M. Staugaitis; Astrid Cardona; Richard M. Ransohoff; Karl Herrup; Bruce T. Lamb

Neurobiology of Disease (Feb 2014)

Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events

Kiran Bhaskar,
Nicole Maphis,
Guixiang Xu,
Nicholas H. Varvel,
Olga N. Kokiko-Cochran,
Jason P. Weick,
Susan M. Staugaitis,
Astrid Cardona,
Richard M. Ransohoff,
Karl Herrup,
Bruce T. Lamb

Affiliations

Kiran Bhaskar: Department of Molecular Genetics and Microbiology, University of New Mexico, MSC08 4660, 1 University of New Mexico, Albuquerque, NM 87131, USA; Corresponding author. Fax: +1 505 272 6029.
Nicole Maphis: Department of Molecular Genetics and Microbiology, University of New Mexico, MSC08 4660, 1 University of New Mexico, Albuquerque, NM 87131, USA
Guixiang Xu: Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Nicholas H. Varvel: Department of Cellular Neurology, University of Tübingen, Hertie Institute for Clinical Brain Research, Otfried-Müller-Straße 27, 72076 Tübingen, Germany
Olga N. Kokiko-Cochran: Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Jason P. Weick: Department of Neurosciences, University of New Mexico, MSC08 4740, 1 University of New Mexico, Albuquerque, NM 87131, USA
Susan M. Staugaitis: Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Astrid Cardona: Department of Biology, University of Texas San Antonio, West Campus/Tobin lab MBT 1.216, San Antonio, TX 78249, USA
Richard M. Ransohoff: Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Karl Herrup: Department of Cell Biology and Neuroscience, Rutgers University, Nelson Hall, Busch Campus, Piscataway, NJ 08855, USA
Bruce T. Lamb: Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Correspondence to: B.T. Lamb, Department of Neurosciences, Cleveland Clinic, NC30, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Fax: +1 215 444 7927.

Journal volume & issue: Vol. 62
pp. 273 – 285

Abstract

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Massive neuronal loss is a key pathological hallmark of Alzheimer's disease (AD). However, the mechanisms are still unclear. Here we demonstrate that neuroinflammation, cell autonomous to microglia, is capable of inducing neuronal cell cycle events (CCEs), which are toxic for terminally differentiated neurons. First, oligomeric amyloid-beta peptide (AβO)-mediated microglial activation induced neuronal CCEs via the tumor-necrosis factor-α (TNFα) and the c-Jun Kinase (JNK) signaling pathway. Second, adoptive transfer of CD11b+ microglia from AD transgenic mice (R1.40) induced neuronal cyclin D1 expression via TNFα signaling pathway. Third, genetic deficiency of TNFα in R1.40 mice (R1.40-Tnfα−/−) failed to induce neuronal CCEs. Finally, the mitotically active neurons spatially co-exist with F4/80+ activated microglia in the human AD brain and that a portion of these neurons are apoptotic. Together our data suggest a cell-autonomous role of microglia, and identify TNFα as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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