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Direct High Affinity Interaction between A?42 and GSK3? Stimulates Hyperphosphorylation of Tau. A New Molecular Link in Alzheimer's Disease?

ABSTRACT: Amyloid ? peptide (A?42) 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 A?42 to identify candidate proteins interacting with toxic A?42 species. Samples prepared from Alexa546-A?42 and A?42 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 A?42 and glycogen synthase kinase 3? (GSK3?), a kinase previously implicated in the disease pathology. This interaction was validated with anti-GSK3? immunoprecipitation assays in neuronal cell lysates. Confocal microscopy studies further identified colocalization of A?42 and GSK3? in neurites of mature primary mouse neurons. A high binding affinity (KD = 1 nM) was measured between Alexa488-A?42 and GSK3? in solution using thermophoresis. An even lower apparent KD was estimated between GSK3? and dextran-immobilized A?42 in surface plasmon resonance experiments. Parallel experiments with GSK3? also identified colocalization and high affinity binding to this isoform. GSK3?-mediated hyperphosphorylation of the protein tau was found to be stimulated by A?42 in in vitro phosphorylation assays and identified a functional relationship between the proteins. We uncover a direct and functional molecular link between A?42 and GSK3?, which opens an important avenue toward understanding the mechanism of A?42-mediated neuronal toxicity in Alzheimer's disease.

SUBMITTER: Dunning CJ

PROVIDER: S-EPMC4759616 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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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 J CJ McGauran Gavin G Willén Katarina K Gouras Gunnar K GK O'Connell David J DJ Linse Sara S

ACS chemical neuroscience 20151215 2

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 o ...[more]

PMID: 26618561

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Project description:ObjectiveMost neurodegenerative diseases contain hyperphosphorylated Tau [p-Tau]. We examined for the first time epitopes at which Tau is hyperphosphorylated in Parkinson's disease, dementia with Lewy bodies and Alzheimer's disease, and also select Tau kinases.MethodsPostmortem frontal cortex from Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease and striata from Parkinson's disease, were analyzed by immunoblots using commercially available antibodies against 20 different phospho-epitopes of Tau. Major Tau kinases were also screened. Results in diseased tissues were compared to nondiseased controls.ResultsIn Alzheimer's disease, Tau was hyperphosphorylated at all the 20 epitopes of p-Tau. In dementia with Lewy bodies, p-Tau formation occurred at 6 sites sharing 30% overlap with Alzheimer's disease, while in Parkinson's frontal cortex, an area which does not degenerate, Tau hyperphosphorylation was seen at just 3 epitopes, indicating 15% overlap with Alzheimer's disease. In Parkinson's disease striatum, an area which undergoes considerable neurodegeneration, Tau was hyperphosphorylated at 10 epitopes, sharing 50% overlap with Alzheimer's disease. Between frontal cortex of Parkinson's disease and dementia with Lewy bodies, there were only two p-Tau epitopes in common. In striata of Parkinson's disease, there were 3 clusters of Tau hyperphosphorylated at 3 contiguous sites, while two such clusters were detected in dementia with Lewy bodies; such clusters disrupt axonal transport of mitochondria, cause microtubule remodeling and result in cell death. p-GSK-3?, a major Tau kinase, was activated in all brain regions examined, except in dementia with Lewy bodies. Activation of other Tau kinases was seen in all brain regions, with no clear pattern of activation.InterpretationOur studies suggest that the three neurodegenerative diseases each have a signature-specific profile of p-Tau formation which may be useful in understanding the genesis of the diseases and for the development of a panel of specific biomarkers.

Dataset Information

Direct High Affinity Interaction between A?42 and GSK3? Stimulates Hyperphosphorylation of Tau. A New Molecular Link in Alzheimer's Disease?

Publications

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

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