Cofilin-mediated neurodegeneration in Alzheimer's disease and other amyloidopathies.
Transport defects may arise in various neurodegenerative diseases from failures in molecular motors, microtubule abnormalities, and the chaperone/proteasomal degradation pathway leading to aggresomal-lysosomal accumulations. These defects represent important steps in the neurodegenerative cascade, although in many cases, a clear consensus has yet to be reached regarding their causal relationship to the disease. A growing body of evidence lends support to a link between neurite transport defects in the very early stages of many neurodegenerative diseases and alterations in the organization and dynamics of the actin cytoskeleton initiated by filament dynamizing proteins in the ADF/cofilin family. This article focuses on cofilin, which in neurons under stress, including stress induced by the amyloid-beta (Abeta) 1-42 peptide, undergoes dephosphorylation (activation) and forms rod-shaped actin bundles (rods). Rods inhibit transport, are sites of amyloid precursor protein accumulation, and contribute to the pathology of Alzheimer's disease. Because rods form rapidly in response to anoxia, they could also contribute to synaptic deficits associated with ischemic brain injury (e.g., stroke). Surprisingly, cofilin undergoes phosphorylation (inactivation) in hippocampal neurons treated with Abeta1-40 at high concentrations, and these neurons undergo dystrophic morphological changes, including accumulation of pretangle phosphorylated-tau. Therefore, extremes in phosphoregulation of cofilin by different forms of Abeta may explain much of the Alzheimer's disease pathology and provide mechanisms for synaptic loss and plaque expansion.
Maloney
Michael T
MT
Department of Biochemistry and Molecular Biology, Cellular and Integrative Neurosciences Program, Colorado State University, Fort Collins, CO, USA.
Bamburg
James R
JR
D051339:Actin Depolymerizing Factors / Q000378:metabolism* / Q000648:ultrastructure; D000199:Actins / Q000378:metabolism / Q000648:ultrastructure; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D022161:Transport Vesicles / Q000378:metabolism
D051339:Actin Depolymerizing Factors; D000199:Actins; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases