title: Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta.
abstract: The pathological mechanism by which Abeta causes neuronal dysfunction and death remains largely unknown. Deficiencies in fast axonal transport (FAT) were suggested to play a crucial role in neuronal dysfunction and loss for a diverse set of dying back neuropathologies including Alzheimer's disease (AD), but the molecular basis for pathological changes in FAT were undetermined. Recent findings indicate that soluble intracellular oligomeric Abeta (oAbeta) species may play a critical role in AD pathology. Real-time analysis of vesicle mobility in isolated axoplasms perfused with oAbeta showed bidirectional axonal transport inhibition as a consequence of endogenous casein kinase 2 (CK2) activation. Conversely, neither unaggregated amyloid beta nor fibrillar amyloid beta affected FAT. Inhibition of FAT by oAbeta was prevented by two specific pharmacological inhibitors of CK2, as well as by competition with a CK2 substrate peptide. Furthermore, perfusion of axoplasms with active CK2 mimics the inhibitory effects of oAbeta on FAT. Both oAbeta and CK2 treatment of axoplasm led to increased phosphorylation of kinesin-1 light chains and subsequent release of kinesin from its cargoes. Therefore pharmacological modulation of CK2 activity may represent a promising target for therapeutic intervention in AD.
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois, Chicago, IL 60612, USA.
authors.forename: G
authors.initials: G
authors.lastname: Pigino
authors.forename: G
authors.initials: G
authors.lastname: Morfini
authors.forename: Y
authors.initials: Y
authors.lastname: Atagi
authors.forename: A
authors.initials: A
authors.lastname: Deshpande
authors.forename: C
authors.initials: C
authors.lastname: Yu
authors.forename: L
authors.initials: L
authors.lastname: Jungbauer
authors.forename: M
authors.initials: M
authors.lastname: LaDu
authors.forename: J
authors.initials: J
authors.lastname: Busciglio
authors.forename: S
authors.initials: S
authors.lastname: Brady