Molecular and physiological ageing in Alzheimer's disease
Aggregation of amyloid-beta (Ab), upstream of tau phosphorylation, is considered the driving force in Alzheimer’s disease (AD). However, the first clinical trials for AD in UK involving amyloid-targeting immunotherapy did not show any improvement in cognition in patients. This indicated the need for better insight into AD pathogenesis at the molecular level. Ageing is the main risk factor for AD, and scientists with the project ALZPROTAGEING (Age-modified forms of amyloid-β as initiator of Alzheimer disease pathogenesis and mediator of Aβ-tau interaction: a study in a Drosophila model and Aβ immunized human Alzheimer patients) investigated the link between the modifications associated with amino acid in Ab, marker of protein ageing, and AD pathogenesis. Project researchers used Drosophila models expressing human Ab to model Ab aggregation and analyse its toxic effect. In human post-mortem brain, they studied the age-related changes in Ab and Amyloid Precursor Protein (APP) in relation to tau phosphorylation in young and old cognitively normal people and AD cases. Research results provided novel insight into factors driving AD pathogenesis. Their findings suggest that ageing drives AD pathology by changing APP cellular localization. This is concomitant with the increase of extracellular Ab, which presents significantly higher level of amino acid modifications in AD patients, supporting the hypothesis that protein ageing can affect Ab accumulation in the brain. They also evaluated whether these modified forms of Ab were removed from the brain of AD patients that participated in the first clinical trial involving Ab-targeting immunotherapy (Elan, AN1792). The comparison of immunised and non-immunised AD brains revealed no significant difference in the level of these modified forms of Ab. The ALZPROTAGEING study highlighted factors driving AD pathogenesis, opening new perspectives in understanding the physiological role of APP and Ab, and validated the use of Drosophila in studying the effect of Ab aggregation in vivo. Furthermore, the study outcomes provided new insight on the characterisation of Ab as therapeutic target, which can benefit to the development of future effective therapies for AD.
Keywords
Alzheimer's disease, ageing, dementia, amyloid-beta, immunotherapyamyloid-beta
