Amyloid β-protein stimulates casein kinase I and casein kinase II activities

Chauhan, Abha; Chauhan, Ved; Murakami, Noriko; Brockerhoff, H.; Wı́sniewski, Henryk M.

doi:10.1016/0006-8993(93)90479-7

Cited by 50 publications

(34 citation statements)

References 29 publications

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“…Based on results showing that heterogeneous A␤ could directly stimulate CK2 kinase activity in vitro (35), the role of endogenous CK2 activation in oA␤-induced FAT inhibition was evaluated. 2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) is a potent and highly specific ATP-competitive inhibitor of CK2 (36) derived from 4,5,6,7-tetrabromo-2-azabenzimidazole (TBB).…”

Section: Oa␤-induced Fat Inhibition Results From Endogenous Ck2 Activmentioning

confidence: 99%

“…2D). In addition, A␤ was reported to increase the kinase activity of CK2 in vitro (35). Although the molecular mechanism by which oA␤ induces CK2 activation remains to be determined, preliminary studies suggest that oA␤ can activate recombinant CK2 in vitro and increase phosphorylation of the CK2 specific peptide in the absence of cell lysates (G.P., Y.A., and S.B., unpublished).…”

Section: Discussionmentioning

confidence: 96%

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Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

Pigino

Morfini

Atagi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

195

172

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The pathological mechanism by which A␤ 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 A␤ (oA␤) species may play a critical role in AD pathology. Real-time analysis of vesicle mobility in isolated axoplasms perfused with oA␤ 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 oA␤ 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 oA␤ on FAT. Both oA␤ 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.Alzheimer's disease ͉ Axonal transport ͉ Beta amyloid oligomer ͉ CK2 ͉ Kinesin T he complex functional changes and histopathology of Alzheimer disease (AD) make it one of the most challenging disorders faced by modern medicine. Histopathological hallmarks of AD include distinctive extracellular and intracellular aggregates of amyloid beta (A␤) and tau (1, 2). Synaptic dysfunction and axonopathy appear to be the earliest lesions in AD as corroborated by reduced immunoreactivity of synaptophysin and other synaptic markers in terminal fields of brain-affected areas (3). AD-affected neurons appear to die eventually as a consequence of synaptic dysfunction and loss, following a typical dying-back pattern of neuronal degeneration.The amyloid hypothesis (4), a dominant concept in AD research for many years, has been revised in recent years to include the notion that smaller soluble A␤ aggregates may play an early and significant role in AD. Soluble oligomers of A␤ (oA␤) have been shown to be neurotoxic both in vivo and in vitro (5-7) as well as altering synaptic structure and function (8). Moreover, oA␤ levels correlate with impairments in cognitive function, learning, and memory (9, 10), but the molecular basis of these effects are uncertain. Intracellular A␤ was first described by Wertkin et al. (11). Immunogold electron microscopy showed that intraneuronal A␤ is pre-and postsynaptically enriched in both AD human brain and AD transgenic animal models in association with dystrophic neurites and abnormal synaptic morphology (12)(13)(14). Spatial and temporal analyses of intraneuronal oA␤ accumulation show that it precedes plaque formation in both AD animal models and Down's syndrome patients, suggesting that oA␤ is an early intracellular toxic agent i...

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Section: Oa␤-induced Fat Inhibition Results From Endogenous Ck2 Activmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

Pigino

Morfini

Atagi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

195

172

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“…It has been reported that CK-1 is significantly elevated in Alzheimer's disease brains (39,40). Moreover, A␤ has been shown to activate CK-1 in vitro (41). However, it remains to be determined if phosphorylation of BACE is altered during pathogenesis of Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation Regulates Intracellular Trafficking of β-Secretase

Walter

Fluhrer

Hartung

et al. 2001

Journal of Biological Chemistry

263

284

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␤-Secretase (BACE) is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid ␤-peptide. Here, we report that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after full maturation of BACE by propeptide cleavage and complex N-glycosylation. Phosphorylation/dephosphorylation affects the subcellular localization of BACE. BACE wild type and an S498D mutant that mimics phosphorylated BACE are predominantly located within juxtanuclear Golgi compartments and endosomes, whereas nonphosphorylatable BACE S498A accumulates in peripheral EEA1-positive endosomes. Antibody uptake assays revealed that reinternalization of BACE from the cell surface is independent of its phosphorylation state. After reinternalization, BACE wild type as well as BACE S498D are efficiently retrieved from early endosomal compartments and further targeted to later endosomal compartments and/or the trans-Golgi network. In contrast, nonphosphorylatable BACE S498A is retained within early endosomes. Our results therefore demonstrate regulated trafficking of BACE within the secretory and endocytic pathway.

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“…Second, the three-dimensional structure of CKI reveals a surface loop nearly identical in structure to the regulatory T-loop of CDK2 (Xu et al, 1995), suggesting that CK1 may be regulated through reversible phosphorylation of its activation 1oop as observed for CDK2 and other protein kinases (Johnson et al, 1996). Finally, it has been shown that /3-amyloid, the major component of neuritic plaques (a second ADassociated pathological lesion), is capable of directly stimulating CKI activity in vitro (Chauhan et al, 1993). Thus, on the basis of its ability to phosphorylate tau in vitro, its cell cycle-dependent association with microtubules in vivo, its tight association with tau pathology, and its activation by other components of AD pathology, the properties of CKIa isoforms are favorable for playing a role in the formation of hyperphosphorylated tau in neurodegenerative disease.…”

Section: Figmentioning

confidence: 99%

Casein Kinase 1 Is Tightly Associated with Paired‐Helical Filaments Isolated from Alzheimer's Disease Brain

Kuret¹,

Johnson

Cha³

et al. 1997

Journal of Neurochemistry

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Abstract:The protein kinase activity tightly associated with paired helical filaments (PHFs) purified from the brain tissue of individuals with Alzheimer's disease has been characterized in vitro. The activity is shown to phosphorylate casein, an exogenous substrate, with a maximal velocity of -~2nmol/min/mg, suggesting it comprises a significant component of the total protein in the PHF preparation. On the basis of substrate selectivity, isoquinoline sulfonamide inhibitor selectivity, in-gel renaturation assays, and western analysis, the activity consists of closely related members of the a branch of the casein kinase 1 family of protein kinases. Because of its tight association with PHFs and its phosphate-directed substrate selectivity, casein kinase 1 is positioned to participate in the pathological hyperphosphorylation of tau protein that is observed in neurodegenerative diseases such as Alzheimer's disease.

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Amyloid β-protein stimulates casein kinase I and casein kinase II activities

Cited by 50 publications

References 29 publications

Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

Phosphorylation Regulates Intracellular Trafficking of β-Secretase

Casein Kinase 1 Is Tightly Associated with Paired‐Helical Filaments Isolated from Alzheimer's Disease Brain

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