Aβ aggregation and propagation in transgenic models of Alzheimer’s disease

Abstract

Alzheimer´s disease (AD) is a complex neurodegenerative disorder that affects mainly the elder population. To date, modifying therapies have not proven to be successful, and therefore, a major effort is necessary to unravel the pathogenic processes underlying AD. New evidences indicate that AD and many other neurodegenerative diseases have commonly the accumulation of misfolded proteins that have the potential to act as infectious agents, and propagate through the entire brain, affecting native proteins. The amyloid peptide (Aβ), characteristic of AD, can adopt a β-sheet conformation acquiring the potential to aggregate and generate misfolded intermediates that can act as ‘’seeds’’ to propagate disease in the brain. Recent findings suggest that these seeds are structurally different depending on the patients and AD subtype, showing different propagation capacity and toxicity. In order to find out which Aβ species or isoforms are more toxic and have greater potential to aggregate, brain extracts from AD patients have been inoculated into transgenic AD mice brains. These approaches have provided much information, however, most of the models contain one or multiple dominant mutations of familial AD cases. This is of great value to mimic the familial forms of the disease, but not the late onset AD (LOAD), which constitute the majority of the cases. Therefore, new animal models are urgently necessary to circumvent these limitations and properly dissect the pathogenic mechanisms of this common form of the disease. As such, a new humanized Aβ model, called hAβ-KI, that has been generated by UCI-MODEL AD center at California, recapitulates certain features of LOAD. This might represent a useful LOAD model to understand how Aβ spreads and favors the progression of the pathology in the brain, hopefully enabling the development of effective therapeutic interventions for AD.