Amyloid-β and proinflammatory cytokines utilize a prion protein-dependent pathway to activate NADPH oxidase and induce cofilin-actin rods in hippocampal neurons.
Neurites of neurons under acute or chronic stress form bundles of filaments (rods) containing 1∶1 cofilin∶actin, which impair transport and synaptic function. Rods contain disulfide cross-linked cofilin and are induced by treatments resulting in oxidative stress. Rods form rapidly (5-30 min) in >80% of cultured hippocampal or cortical neurons treated with excitotoxic levels of glutamate or energy depleted (hypoxia/ischemia or mitochondrial inhibitors). In contrast, slow rod formation (50% of maximum response in ∼6 h) occurs in a subpopulation (∼20%) of hippocampal neurons upon exposure to soluble human amyloid-β dimer/trimer (Aβd/t) at subnanomolar concentrations. Here we show that proinflammatory cytokines (TNFα, IL-1β, IL-6) also induce rods at the same rate and within the same neuronal population as Aβd/t. Neurons from prion (PrP(C))-null mice form rods in response to glutamate or antimycin A, but not in response to proinflammatory cytokines or Aβd/t. Two pathways inducing rod formation were confirmed by demonstrating that NADPH-oxidase (NOX) activity is required for prion-dependent rod formation, but not for rods induced by glutamate or energy depletion. Surprisingly, overexpression of PrP(C) is by itself sufficient to induce rods in over 40% of hippocampal neurons through the NOX-dependent pathway. Persistence of PrP(C)-dependent rods requires the continuous activity of NOX. Removing inducers or inhibiting NOX activity in cells containing PrP(C)-dependent rods causes rod disappearance with a half-life of about 36 min. Cofilin-actin rods provide a mechanism for synapse loss bridging the amyloid and cytokine hypotheses for Alzheimer disease, and may explain how functionally diverse Aβ-binding membrane proteins induce synaptic dysfunction.
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, United States of America.
Keifer P
KP
Walsh
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, United States of America.
Laurie S
LS
Minamide
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, United States of America; Molecular, Cellular and Integrative Neuroscience Program, Colorado State University, Fort Collins, Colorado, United States of America.
Sarah J
SJ
Kane
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, United States of America.
Alisa E
AE
Shaw
Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom.
David R
DR
Brown
Prion Research Center, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
Bruce
B
Pulford
Molecular, Cellular and Integrative Neuroscience Program, Colorado State University, Fort Collins, Colorado, United States of America; Prion Research Center, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
Mark D
MD
Zabel
Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
J David
JD
Lambeth
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, United States of America; Department of Chemistry and Biochemistry, University of Alaska, Fairbanks, Alaska, United States of America.
Thomas B
TB
Kuhn
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, United States of America; Molecular, Cellular and Integrative Neuroscience Program, Colorado State University, Fort Collins, Colorado, United States of America.
James R
JR
Bamburg
D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D016501:Neurites / Q000378:metabolism*; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D009435:Synaptic Transmission / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051339:Actin Depolymerizing Factors; D000199:Actins; D016229:Amyloid beta-Peptides; D018621:PrPC Proteins; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D018698:Glutamic Acid; D019255:NADPH Oxidases