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A luminescence-based reporter to study tau secretion reveals overlapping mechanisms for the release of healthy and pathological tau

A luminescence-based reporter to study tau secretion reveals overlapping mechanisms for the release of healthy and pathological tau
A luminescence-based reporter to study tau secretion reveals overlapping mechanisms for the release of healthy and pathological tau
In Alzheimer’s disease, tau pathology is thought to spread via a prion-like manner along connected neuronal networks. For this to occur, the usually cytosolic tau protein must be secreted via an unconventional mechanism prior to uptake into the connected neuron. While secretion of healthy and pathological tau has been documented, it remains under-investigated whether this occurs via overlapping or distinct processes. Here, we established a sensitive bioluminescence-based assay to assess mechanisms underlying the secretion of pseudohyperphosphorylated and wild-type tau in cultured murine hippocampal neurons. We found that under basal conditions, both wild-type and mutant tau are secreted, with mutant tau being more robustly secreted. Pharmacological stimulation of neuronal activity led to a modest increase of wild-type and mutant tau secretion, whereas inhibition of activity had no effect. Interestingly, inhibition of heparin sulfate proteoglycan (HSPG) biosynthesis drastically decreased secretion of both wild-type and mutant tau without affecting cell viability. This shows that native and pathological tau share release mechanisms; both activity-dependent and non-activity-dependent secretion of tau is facilitated by HSPGs.
tauopathy, tau secretion, split luciferase reporter, neuronal activity, biosensor, tauopathy, biosensor, split luciferase reporter, neuronal activity, tau secretion
1662-4548
Lopez, Dianne
e3c897e7-44d8-4818-b8f2-cf73361a4bbe
Maltby, Connor
785e7b68-509e-450f-8b0c-7d8e46db58a7
Warming, Hannah Kate
52e41d3f-0cf4-440f-b0c9-cec47ed3b23a
Divecha, Nullin
5c2ad0f8-4ce7-405f-8a15-2fc4ab96d787
Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1
Coldwell, Mark
5771d24c-8b19-4f19-95db-b1b3679e6df4
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Lopez, Dianne
e3c897e7-44d8-4818-b8f2-cf73361a4bbe
Maltby, Connor
785e7b68-509e-450f-8b0c-7d8e46db58a7
Warming, Hannah Kate
52e41d3f-0cf4-440f-b0c9-cec47ed3b23a
Divecha, Nullin
5c2ad0f8-4ce7-405f-8a15-2fc4ab96d787
Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1
Coldwell, Mark
5771d24c-8b19-4f19-95db-b1b3679e6df4
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1

Lopez, Dianne, Maltby, Connor, Warming, Hannah Kate, Divecha, Nullin, Vargas-Caballero, Mariana, Coldwell, Mark and Deinhardt, Katrin (2023) A luminescence-based reporter to study tau secretion reveals overlapping mechanisms for the release of healthy and pathological tau. Frontiers in Neuroscience, 17, [1196007]. (doi:10.3389/fnins.2023.1196007).

Record type: Article

Abstract

In Alzheimer’s disease, tau pathology is thought to spread via a prion-like manner along connected neuronal networks. For this to occur, the usually cytosolic tau protein must be secreted via an unconventional mechanism prior to uptake into the connected neuron. While secretion of healthy and pathological tau has been documented, it remains under-investigated whether this occurs via overlapping or distinct processes. Here, we established a sensitive bioluminescence-based assay to assess mechanisms underlying the secretion of pseudohyperphosphorylated and wild-type tau in cultured murine hippocampal neurons. We found that under basal conditions, both wild-type and mutant tau are secreted, with mutant tau being more robustly secreted. Pharmacological stimulation of neuronal activity led to a modest increase of wild-type and mutant tau secretion, whereas inhibition of activity had no effect. Interestingly, inhibition of heparin sulfate proteoglycan (HSPG) biosynthesis drastically decreased secretion of both wild-type and mutant tau without affecting cell viability. This shows that native and pathological tau share release mechanisms; both activity-dependent and non-activity-dependent secretion of tau is facilitated by HSPGs.

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Accepted/In Press date: 17 May 2023
e-pub ahead of print date: 5 June 2023
Published date: 5 June 2023
Additional Information: Funding Information: This work was supported by the Gerald Kerkut Trust and the Institute for Life Sciences. Publisher Copyright: Copyright © 2023 Lopez, Maltby, Warming, Divecha, Vargas-Caballero, Coldwell and Deinhardt.
Keywords: tauopathy, tau secretion, split luciferase reporter, neuronal activity, biosensor, tauopathy, biosensor, split luciferase reporter, neuronal activity, tau secretion

Identifiers

Local EPrints ID: 477790
URI: http://eprints.soton.ac.uk/id/eprint/477790
ISSN: 1662-4548
PURE UUID: 030f53ac-ec64-4239-af30-3d832fd1e8e1
ORCID for Mariana Vargas-Caballero: ORCID iD orcid.org/0000-0003-2326-4001
ORCID for Katrin Deinhardt: ORCID iD orcid.org/0000-0002-6473-5298

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Date deposited: 14 Jun 2023 16:47
Last modified: 06 Jun 2024 01:51

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Contributors

Author: Dianne Lopez
Author: Connor Maltby
Author: Nullin Divecha
Author: Mark Coldwell

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