Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s40478-017-0505-x
Keywords
IsoAspartate; Pyroglutamate; Alzheimer's disease; Amyloid-beta; Ageing
Categories
Funding
- Marie Curie Intra European Fellowship within the 7th European Community Framework [627152]
- Alzheimer's Research UK [ARUK-PG2012-8]
- MRC [G1100578, G0701018, MR/N004272/1] Funding Source: UKRI
- Alzheimers Research UK [ART-PG2006-4, ARUK-PG2012-8, ARUK-EG2015A-4] Funding Source: researchfish
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Alzheimer's disease (AD) is the most common cause of dementia among older adults. Accumulation of amyloid-beta (A beta) 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 A beta, 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-A beta) and pyroglutamate (pE3-A beta) modified forms of A beta 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-A beta and IsoD-A beta, quantified as protein load and correlated with other A beta forms and p-TAU. IsoD-A beta and pE3-A beta were detected at low levels in non-demented controls, and significantly increased in AD (p <= 0.001), with a characteristic deposition of IsoD-A beta in blood vessel walls and pE3-A beta within neurons. Both AD and OC showed positive associations between IsoD-A beta and A beta ( p = 0.003 in AD and p = 0.001 in OC) and between IsoD-A beta and pE3-A beta ( p = 0.001 in AD and OC). This last association was the only significant pE3-A beta correlation identified in AD, whereas in the control cohorts pE3-A beta also correlated with A beta and A beta PP ( p = 0.001 in OC and p = 0.010 in YC). Our analyses suggest that IsoD-A beta accumulation starts with ageing; whereas pE3-A beta deposition is more closely linked to AD. Our findings support the importance of age-related modifications of A beta in AD pathogenesis.
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