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
(2016)
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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/8506072
- author
- Dunning, Christopher
LU
; McGauran, Gavin
; Willén, Katarina
LU
; Gouras, Gunnar
LU
; O'Connell, David J
and Linse, Sara
- organization
- publishing date
- 2016
- type
- Contribution to journal
- publication status
- published
- subject
- in
- ACS Chemical Neuroscience
- volume
- 7
- issue
- 2
- pages
- 161 - 170
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:26618561
- scopus:84959318783
- wos:000370583300004
- pmid:26618561
- 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
- 2016-04-04 09:14:20
- date last changed
- 2022-03-15 18:20:44
@article{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}},
number = {{2}},
pages = {{161--170}},
publisher = {{The American Chemical Society (ACS)}},
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}},
doi = {{10.1021/acschemneuro.5b00262}},
volume = {{7}},
year = {{2016}},
}