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Peri-arterial pathways for clearance of α-Synuclein and tau from the brain: implications for the pathogenesis of dementias and for immunotherapy

Peri-arterial pathways for clearance of α-Synuclein and tau from the brain: implications for the pathogenesis of dementias and for immunotherapy
Peri-arterial pathways for clearance of α-Synuclein and tau from the brain: implications for the pathogenesis of dementias and for immunotherapy

Introduction: Accumulation of amyloid beta (Aβ), α-synuclein (αSyn), and tau in dementias indicates their age-related failure of elimination from the brain. Aβ is eliminated along basement membranes in walls of cerebral arterioles and leptomeningeal arteries (intramural peri-arterial drainage [IPAD]); IPAD is impaired with age. We test the hypothesis that αSyn and tau are also eliminated from the normal brain along IPAD pathways.

Methods: Soluble αSyn or tau was injected into mouse hippocampus. Animals were perfused 5 minutes to 7 days post-injection. Blood vessels were identified by ROX-SE for light-sheet and immunolabeling for confocal microscopy. IPAD was quantified by measuring the proportion of arterioles with αSyn/tau.

Results: αSyn and tau are eliminated from the brain by IPAD but with different dynamics.

Discussion: Age-related failure of IPAD may play a role in the pathogenesis of synucleinopathies and tauopathies. αSyn persists within IPAD at 24 hours, which may affect immunotherapy for αSyn.

2352-8729
Nimmo, Jacqui Taryn
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Johnston, David
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Dodart, J.C.
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MacGregor Sharp, Matthew
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Weller, Roy O.
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Nicoll, James
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Verma, Ajay
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Carare, Roxana-Octavia
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Nimmo, Jacqui Taryn
222608e3-256e-4ba4-a259-cbdfcb5340c6
Johnston, David
b41163c9-b9d2-425c-af99-2a357204014e
Dodart, J.C.
7e5f6861-a4e2-4ee7-8d2d-576274e92dc6
MacGregor Sharp, Matthew
ec57c53a-a10a-4b8a-94fe-03eca85ab7c3
Weller, Roy O.
4a501831-e38a-4d39-a125-d7141d6c667b
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Verma, Ajay
5a207350-0de9-487a-be28-f9eb2f558140
Carare, Roxana-Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa

Nimmo, Jacqui Taryn, Johnston, David, Dodart, J.C., MacGregor Sharp, Matthew, Weller, Roy O., Nicoll, James, Verma, Ajay and Carare, Roxana-Octavia (2020) Peri-arterial pathways for clearance of α-Synuclein and tau from the brain: implications for the pathogenesis of dementias and for immunotherapy. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 12 (1), [e12070]. (doi:10.1002/dad2.12070).

Record type: Article

Abstract

Introduction: Accumulation of amyloid beta (Aβ), α-synuclein (αSyn), and tau in dementias indicates their age-related failure of elimination from the brain. Aβ is eliminated along basement membranes in walls of cerebral arterioles and leptomeningeal arteries (intramural peri-arterial drainage [IPAD]); IPAD is impaired with age. We test the hypothesis that αSyn and tau are also eliminated from the normal brain along IPAD pathways.

Methods: Soluble αSyn or tau was injected into mouse hippocampus. Animals were perfused 5 minutes to 7 days post-injection. Blood vessels were identified by ROX-SE for light-sheet and immunolabeling for confocal microscopy. IPAD was quantified by measuring the proportion of arterioles with αSyn/tau.

Results: αSyn and tau are eliminated from the brain by IPAD but with different dynamics.

Discussion: Age-related failure of IPAD may play a role in the pathogenesis of synucleinopathies and tauopathies. αSyn persists within IPAD at 24 hours, which may affect immunotherapy for αSyn.

Text
DADM-D-20-00101_R1 - Accepted Manuscript
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More information

Accepted/In Press date: 22 June 2020
e-pub ahead of print date: 28 July 2020
Published date: 2020
Additional Information: © 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.

Identifiers

Local EPrints ID: 442059
URI: http://eprints.soton.ac.uk/id/eprint/442059
ISSN: 2352-8729
PURE UUID: 41570b5d-7fee-48d6-9191-a6a8e2e2cfbc
ORCID for David Johnston: ORCID iD orcid.org/0000-0001-6703-6014
ORCID for Matthew MacGregor Sharp: ORCID iD orcid.org/0000-0002-6623-5078
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246
ORCID for Roxana-Octavia Carare: ORCID iD orcid.org/0000-0001-6458-3776

Catalogue record

Date deposited: 06 Jul 2020 16:31
Last modified: 26 Nov 2021 05:57

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Contributors

Author: Jacqui Taryn Nimmo
Author: David Johnston ORCID iD
Author: J.C. Dodart
Author: Matthew MacGregor Sharp ORCID iD
Author: Roy O. Weller
Author: James Nicoll ORCID iD
Author: Ajay Verma

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