Mapping cofilin-actin rods in stressed hippocampal slices and the role of cdc42 in amyloid-beta-induced rods.
Dissociated hippocampal neurons exposed to a variety of degenerative stimuli form neuritic cofilin-actin rods. Here we report on stimulus driven regional rod formation in organotypic hippocampal slices. Ultrastructural analysis of rods formed in slices demonstrates mitochondria and vesicles become entrapped within some rods. We developed a template for combining and mapping data from multiple slices, enabling statistical analysis for the identification of vulnerable sub-regions. Amyloid-beta (Abeta) induces rods predominantly in the dentate gyrus region, and Abeta-induced rods are reversible following washout. Rods that persist 24 h following transient (30 min) ATP-depletion are broadly distributed, whereas rods formed in response to excitotoxic glutamate localize within and nearby the pyramidal neurons. Time-lapse imaging of cofilin-GFP-expressing neurons within slices shows neuronal rod formation begins rapidly and peaks by 10 min of anoxia. In approximately 50% of responding neurons, Abeta-induced rod formation acts via cdc42, an upstream regulator of cofilin. These new observations support a role for cofilin-actin rods in stress-induced disruption of cargo transport and synaptic function within hippocampal neurons and suggest both cdc42-dependent and independent pathways modulate cofilin activity downstream from Abeta.
Davis
Richard C
RC
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA.|Molecular, Cellular and Integrative Neuroscience Program, Colorado State University, Fort Collins, CO, USA.
Maloney
Michael T
MT
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA.|Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Minamide
Laurie S
LS
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA.
Flynn
Kevin C
KC
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA.|Molecular, Cellular and Integrative Neuroscience Program, Colorado State University, Fort Collins, CO, USA.|Max Planck Institute of Neurobiology, Martinsreid, Munich, Germany.
Stonebraker
Matthew A
MA
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA.
Bamburg
James R
JR
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA.|Molecular, Cellular and Integrative Neuroscience Program, Colorado State University, Fort Collins, CO, USA.
D000199:Actins / Q000502:physiology / Q000648:ultrastructure*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001931:Brain Mapping / Q000379:methods*; D002645:Chickens; D051338:Cofilin 1 / Q000502:physiology / Q000648:ultrastructure*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D009924:Organ Culture Techniques; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*
D000199:Actins; D016229:Amyloid beta-Peptides; C495811:Cfl1 protein, mouse; C495812:Cfl1 protein, rat; D051338:Cofilin 1; D020764:cdc42 GTP-Binding Protein