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PMID: 19321417 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 106 ·No. 14 ·2009-04-07 ·Pages 5907-12

Pigino G, Morfini G, Atagi Y, Deshpande A, Yu C, Jungbauer L, LaDu M, Busciglio J, Brady S

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.

MeSH Terms
Alzheimer Disease Amyloid beta-Peptides/pharmacology Animals Axonal Transport/drug effects Casein Kinase II/metabolism Kinesins/metabolism Mice Neurons/pathology Phosphorylation Protein Multimerization
Chemicals
Amyloid beta-Peptides Casein Kinase II Kinesins
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Pigino G
Department of Anatomy and Cell Biology, University of Illinois, Chicago, IL 60612, USA.
Morfini G
Atagi Y
Deshpande A
Yu C
Jungbauer L
LaDu M
Busciglio J
Brady S
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0901229106
Published
2009-04-07
Epub
2009-00-24
Pages
5907-12
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2667037
Subset
IM
Grants
NIA NIH HHS · P01 AG030128-01A2 · United States
NINDS NIH HHS · R01 NS043408 · United States
NINDS NIH HHS · R01 NS023320 · United States
NINDS NIH HHS · NS43408 · United States
NIA NIH HHS · P01 AG030128 · United States
NINDS NIH HHS · R01 NS041170 · United States
NINDS NIH HHS · R01 NS023868 · United States
NINDS NIH HHS · R01 NS023868-22 · United States
NINDS NIH HHS · NS41170 · United States
NINDS NIH HHS · NS23320 · United States
NINDS NIH HHS · R01 NS023868-22S2 · United States
External Links
PubMed source DOI: 10.1073/pnas.0901229106 PMC Full Text View journal details
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