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Direct High Affinity Interaction between Aβ42 and GSK3α Stimulates Hyperphosphorylation of Tau. A New Molecular Link in Alzheimer's Disease?

Dunning, Christopher LU ; McGauran, Gavin; Willén, Katarina LU ; Gouras, Gunnar LU ; O'Connell, David J and Linse, Sara (2015) In ACS Chemical Neuroscience 7(2). p.161-170
Abstract
Amyloid β peptide (Aβ42) assemblies are considered central to the development of Alzheimer's disease, but the mechanism of this toxicity remains unresolved. We screened protein microarrays with on-pathway oligomeric Aβ42 to identify candidate proteins interacting with toxic Aβ42 species. Samples prepared from Alexa546-Aβ42 and Aβ42 monomers at 1:5 molar ratio were incubated with the array during a time window of the amyloid fibril formation reaction during which the maximum number of transient oligomers exist in the reaction flux. A specific interaction was detected between Aβ42 and glycogen synthase kinase 3α (GSK3α), a kinase previously implicated in the disease pathology. This interaction was validated with anti-GSK3α... (More)
Amyloid β peptide (Aβ42) assemblies are considered central to the development of Alzheimer's disease, but the mechanism of this toxicity remains unresolved. We screened protein microarrays with on-pathway oligomeric Aβ42 to identify candidate proteins interacting with toxic Aβ42 species. Samples prepared from Alexa546-Aβ42 and Aβ42 monomers at 1:5 molar ratio were incubated with the array during a time window of the amyloid fibril formation reaction during which the maximum number of transient oligomers exist in the reaction flux. A specific interaction was detected between Aβ42 and glycogen synthase kinase 3α (GSK3α), a kinase previously implicated in the disease pathology. This interaction was validated with anti-GSK3α immunoprecipitation assays in neuronal cell lysates. Confocal microscopy studies further identified colocalization of Aβ42 and GSK3α in neurites of mature primary mouse neurons. A high binding affinity (KD = 1 nM) was measured between Alexa488-Aβ42 and GSK3α in solution using thermophoresis. An even lower apparent KD was estimated between GSK3α and dextran-immobilized Aβ42 in surface plasmon resonance experiments. Parallel experiments with GSK3β also identified colocalization and high affinity binding to this isoform. GSK3α-mediated hyperphosphorylation of the protein tau was found to be stimulated by Aβ42 in in vitro phosphorylation assays and identified a functional relationship between the proteins. We uncover a direct and functional molecular link between Aβ42 and GSK3α, which opens an important avenue toward understanding the mechanism of Aβ42-mediated neuronal toxicity in Alzheimer's disease. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
ACS Chemical Neuroscience
volume
7
issue
2
pages
161 - 170
publisher
The American Chemical Society
external identifiers
  • PMID:26618561
  • Scopus:84959318783
  • WOS:000370583300004
ISSN
1948-7193
DOI
10.1021/acschemneuro.5b00262
language
English
LU publication?
yes
id
879cf336-a0d1-4f0d-a601-fb115845ab06 (old id 8506072)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26618561?dopt=Abstract
date added to LUP
2016-01-04 19:27:52
date last changed
2016-11-06 04:25:48
@misc{879cf336-a0d1-4f0d-a601-fb115845ab06,
  abstract     = {Amyloid β peptide (Aβ42) assemblies are considered central to the development of Alzheimer's disease, but the mechanism of this toxicity remains unresolved. We screened protein microarrays with on-pathway oligomeric Aβ42 to identify candidate proteins interacting with toxic Aβ42 species. Samples prepared from Alexa546-Aβ42 and Aβ42 monomers at 1:5 molar ratio were incubated with the array during a time window of the amyloid fibril formation reaction during which the maximum number of transient oligomers exist in the reaction flux. A specific interaction was detected between Aβ42 and glycogen synthase kinase 3α (GSK3α), a kinase previously implicated in the disease pathology. This interaction was validated with anti-GSK3α immunoprecipitation assays in neuronal cell lysates. Confocal microscopy studies further identified colocalization of Aβ42 and GSK3α in neurites of mature primary mouse neurons. A high binding affinity (KD = 1 nM) was measured between Alexa488-Aβ42 and GSK3α in solution using thermophoresis. An even lower apparent KD was estimated between GSK3α and dextran-immobilized Aβ42 in surface plasmon resonance experiments. Parallel experiments with GSK3β also identified colocalization and high affinity binding to this isoform. GSK3α-mediated hyperphosphorylation of the protein tau was found to be stimulated by Aβ42 in in vitro phosphorylation assays and identified a functional relationship between the proteins. We uncover a direct and functional molecular link between Aβ42 and GSK3α, which opens an important avenue toward understanding the mechanism of Aβ42-mediated neuronal toxicity in Alzheimer's disease.},
  author       = {Dunning, Christopher and McGauran, Gavin and Willén, Katarina and Gouras, Gunnar and O'Connell, David J and Linse, Sara},
  issn         = {1948-7193},
  language     = {eng},
  month        = {12},
  number       = {2},
  pages        = {161--170},
  publisher    = {ARRAY(0xadafd18)},
  series       = {ACS Chemical Neuroscience},
  title        = {Direct High Affinity Interaction between Aβ42 and GSK3α Stimulates Hyperphosphorylation of Tau. A New Molecular Link in Alzheimer's Disease?},
  url          = {http://dx.doi.org/10.1021/acschemneuro.5b00262},
  volume       = {7},
  year         = {2015},
}