ABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia among older adults. Accumulation of amyloid-ß (Aß) 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 Aß, 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-Aß) and pyroglutamate (pE3-Aß) modified forms of Aß 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-Aß and IsoD-Aß, quantified as protein load and correlated with other Aß forms and p-TAU. IsoD-Aß and pE3-Aß were detected at low levels in non-demented controls, and significantly increased in AD (p ≤ 0.001), with a characteristic deposition of IsoD-Aß in blood vessel walls and pE3-Aß within neurons. Both AD and OC showed positive associations between IsoD-Aß and Aß (p = 0.003 in AD and p = 0.001 in OC) and between IsoD-Aß and pE3-Aß (p = 0.001 in AD and OC). This last association was the only significant pE3-Aß correlation identified in AD, whereas in the control cohorts pE3-Aß also correlated with Aß and AßPP (p = 0.001 in OC and p = 0.010 in YC).Our analyses suggest that IsoD-Aß accumulation starts with ageing; whereas pE3-Aß deposition is more closely linked to AD. Our findings support the importance of age-related modifications of Aß in AD pathogenesis.
