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AD is the commonest form of dementia. Aggregation of amyloid-beta (Ab), upstream of tau hyperphosphorylation, is considered a key driver of AD pathogenesis and the major target of the clinical trials of immunotherapy.

Age is the main AD risk factor, but what links physiological ageing and Ab aggregation remains unclear. As the number of people affected by AD increases with the rapidly ageing population, this disease is becoming an economic and social burden. Therefore, investigating the pathological mechanisms of AD and a better understanding of the pharmacological targets are research priorities.

In my Marie Curie Postdoc Fellowship at the University of Southampton, I proposed to investigate neurodegeneration in the context of molecular and physiological ageing. I believe that the misfolding and the pathogenic properties of Ab and of other molecules involved in AD are linked to their protein ageing process, resulting in spontaneous amino acid modifications in these proteins, like pyroglutamate (pE) and IsoAspartate (IsoAsp) formation. Consequently, the identification of markers of protein ageing can be important in the comprehension of AD pathogenesis, with a direct relevance in diagnosis and therapies. For example, Ab active immunotherapy was not able to improve the cognitive performances of the treated patients, possibly due to the absence of clearance of aged modified Ab from the brain. AlzProtAgeing project has studied age-related changes in Ab and in its precursor, APP, and has verified the hypothesis that the accumulation of markers of protein ageing in Ab, is directly associated with AD pathology.

In collaboration with Dr A.Mudher (CfBS, UoS), I have studied the molecular ageing of Ab and its association with misfolding and toxicity, using Drosophila expressing human Ab. In Dr D. Boche lab’s, I have analysed post-mortem brain tissues of AD cases and of cognitive normal controls, both young and old (respectively under and over 65 years old), provided by BRAIN UK and Brains for Dementia Research (BDR). In these tissues, I have examined Ab and its precursor, APP, and pE-Ab and IsoAsp-Ab, to identify molecular changes that spontaneously increases with ageing, driving AD pathogenesis. I have also examined how age-related changes in Ab and APP correlate with the hyperphosporylation of tau. In addition, taking advantage of the unique cohort of unimmunised and immunised AD brains in Dr Boche’s lab, I have analysed the effect of active Ab immunotherapy on age-modified forms of Ab. Manuscripts with these data are being prepared for publications.

The outcomes of this study can have an impact on expanding the characterization of Ab as a pharmacological target, and supporting the rational design of a second generation of “Ab immunotherapies”.

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