Pyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and Alzheimer’s disease
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 agei...
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| Format: | Article |
| Language: | English |
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BMC
2018-01-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-017-0505-x |
| _version_ | 1819118396994748416 |
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| author | Maria Luisa Moro Andrew Stephen Phillips Katie Gaimster Christian Paul Amritpal Mudher James A. R. Nicoll Delphine Boche |
| author_facet | Maria Luisa Moro Andrew Stephen Phillips Katie Gaimster Christian Paul Amritpal Mudher James A. R. Nicoll Delphine Boche |
| author_sort | Maria Luisa Moro |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T05:48:13Z |
| format | Article |
| id | doaj.art-cb25396258db406a8bf693d0e19808cb |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-22T05:48:13Z |
| publishDate | 2018-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-cb25396258db406a8bf693d0e19808cb2022-12-21T18:36:57ZengBMCActa Neuropathologica Communications2051-59602018-01-016111010.1186/s40478-017-0505-xPyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and Alzheimer’s diseaseMaria Luisa Moro0Andrew Stephen Phillips1Katie Gaimster2Christian Paul3Amritpal Mudher4James A. R. Nicoll5Delphine Boche6Clinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of SouthamptonClinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of SouthamptonClinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of SouthamptonClinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of SouthamptonCentre for Biological Sciences, Faculty of Natural & Environmental Sciences, University of SouthamptonClinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of SouthamptonClinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of SouthamptonAbstract 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.http://link.springer.com/article/10.1186/s40478-017-0505-xIsoAspartatePyroglutamateAlzheimer’s diseaseAmyloid-betaAgeing |
| spellingShingle | Maria Luisa Moro Andrew Stephen Phillips Katie Gaimster Christian Paul Amritpal Mudher James A. R. Nicoll Delphine Boche Pyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and Alzheimer’s disease Acta Neuropathologica Communications IsoAspartate Pyroglutamate Alzheimer’s disease Amyloid-beta Ageing |
| title | Pyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and Alzheimer’s disease |
| title_full | Pyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and Alzheimer’s disease |
| title_fullStr | Pyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and Alzheimer’s disease |
| title_full_unstemmed | Pyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and Alzheimer’s disease |
| title_short | Pyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and Alzheimer’s disease |
| title_sort | pyroglutamate and isoaspartate modified amyloid beta in ageing and alzheimer s disease |
| topic | IsoAspartate Pyroglutamate Alzheimer’s disease Amyloid-beta Ageing |
| url | http://link.springer.com/article/10.1186/s40478-017-0505-x |
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