The University of Southampton
University of Southampton Institutional Repository

Pyroglutamate and isoaspartate modified amyloid-beta in ageing and Alzheimer's disease

Pyroglutamate and isoaspartate modified amyloid-beta in ageing and Alzheimer's disease
Pyroglutamate and isoaspartate modified amyloid-beta in ageing and Alzheimer's disease
Alzheimer's disease (AD) is the most common cause of dementia among older adults. Accumulation of amyloid-β (Aβ) in the brain is considered central in AD pathogenesis and its understanding crucial for developing new diagnostic and therapeutic approaches. Recent literature suggests that ageing may induce post translational modifications in Aβ, in the form of spontaneous amino acid modifications, which enhance its pathogenic properties, contributing to its aggregation.
In this study, we have investigated whether the isoaspartate (IsoD-Aβ) and pyroglutamate (pE3-Aβ) modified forms of Aβ are significantly associated with AD pathology or represent markers of ageing. Cerebral neocortex of 27 AD cases, 32 old controls (OC) and 11 young controls (YC) was immunostained for pE3-Aβ and IsoD-Aβ, quantified as protein load and correlated with other Aβ forms and p-TAU. IsoD-Aβ and pE3-Aβ were detected at low levels in non-demented controls, and significantly increased in AD (p≤0.001), with a characteristic deposition of IsoD-Aβ in blood vessel walls and pE3-Aβ within neurons. Both AD and OC showed positive associations between IsoD-Aβ and Aβ (p=0.003 in AD and p=0.001 in OC) and between IsoD-Aβ and pE3-Aβ (p=0.001 in AD and OC). This last association was the only significant pE3-Aβ correlation identified in AD, whereas in the control cohorts pE3-Aβ also correlated with Aβ and AβPP (p=0.001 in OC and p =0.010 in YC).
Our analyses suggest that IsoD-Aβ accumulation starts with ageing; whereas pE3-Aβ deposition is more closely linked to AD. Our findings support the importance of age-related modifications of Aβ in AD pathogenesis.
2051-5960
1-39
Moro, Maria
a9149f60-b1be-4d34-b2f1-ecb1048b4b4f
Phillips, Andrew Stephen
3d6d71cf-e476-41a9-9899-d65f9fa119e7
Gaimster, Katie
c0abf3a6-dbb5-4acb-9cdf-dcb790eebcdb
Paul, Christian
6bb78aea-98cc-4163-82e7-5eb36e90067d
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Moro, Maria
a9149f60-b1be-4d34-b2f1-ecb1048b4b4f
Phillips, Andrew Stephen
3d6d71cf-e476-41a9-9899-d65f9fa119e7
Gaimster, Katie
c0abf3a6-dbb5-4acb-9cdf-dcb790eebcdb
Paul, Christian
6bb78aea-98cc-4163-82e7-5eb36e90067d
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61

Moro, Maria, Phillips, Andrew Stephen, Gaimster, Katie, Paul, Christian, Mudher, Amritpal, Nicoll, James and Boche, Delphine (2018) Pyroglutamate and isoaspartate modified amyloid-beta in ageing and Alzheimer's disease. Acta Neuropathologica Communications, 6 (3), 1-39. (doi:10.1186/s40478-017-0505-x).

Record type: Article

Abstract

Alzheimer's disease (AD) is the most common cause of dementia among older adults. Accumulation of amyloid-β (Aβ) in the brain is considered central in AD pathogenesis and its understanding crucial for developing new diagnostic and therapeutic approaches. Recent literature suggests that ageing may induce post translational modifications in Aβ, in the form of spontaneous amino acid modifications, which enhance its pathogenic properties, contributing to its aggregation.
In this study, we have investigated whether the isoaspartate (IsoD-Aβ) and pyroglutamate (pE3-Aβ) modified forms of Aβ are significantly associated with AD pathology or represent markers of ageing. Cerebral neocortex of 27 AD cases, 32 old controls (OC) and 11 young controls (YC) was immunostained for pE3-Aβ and IsoD-Aβ, quantified as protein load and correlated with other Aβ forms and p-TAU. IsoD-Aβ and pE3-Aβ were detected at low levels in non-demented controls, and significantly increased in AD (p≤0.001), with a characteristic deposition of IsoD-Aβ in blood vessel walls and pE3-Aβ within neurons. Both AD and OC showed positive associations between IsoD-Aβ and Aβ (p=0.003 in AD and p=0.001 in OC) and between IsoD-Aβ and pE3-Aβ (p=0.001 in AD and OC). This last association was the only significant pE3-Aβ correlation identified in AD, whereas in the control cohorts pE3-Aβ also correlated with Aβ and AβPP (p=0.001 in OC and p =0.010 in YC).
Our analyses suggest that IsoD-Aβ accumulation starts with ageing; whereas pE3-Aβ deposition is more closely linked to AD. Our findings support the importance of age-related modifications of Aβ in AD pathogenesis.

Text ANEC-D-17-00149_R1 - Accepted Manuscript
Download (1MB)

More information

Accepted/In Press date: 15 December 2017
e-pub ahead of print date: 3 January 2018

Identifiers

Local EPrints ID: 416497
URI: https://eprints.soton.ac.uk/id/eprint/416497
ISSN: 2051-5960
PURE UUID: 57deea5d-99dc-428e-8314-24774133cf7c
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X

Catalogue record

Date deposited: 20 Dec 2017 17:30
Last modified: 06 Oct 2018 00:37

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×