LAUSR

Abstract Unravelling the molecular basis for Alzheimer’s disease (AD) represents one of the main scientific challenges we face when it comes to treating and – most importantly – preventing the onset of this devastating condition. The amyloid-beta peptide (Aβ) is a key element around which the metabolic pathways linked to sporadic AD forms have been investigated. The right balance between production and degradation of Aβ is fundamental to the physiological activity of the peptide and to preventing the formation of toxic aggregated species. Whilst the metabolic pathways for the formation of Aβ from the amyloid precursor protein (APP) have been unveiled, the mechanism involved in the control of Aβ levels through enzymatic systems (UPS, lysosomes and Aβ-degrading enzymes), both in vitro and in vivo, is underexplored. Overwhelming evidence clearly indicates that the abnormal aggregation of Aβ is not the main – or even the only – biochemical event that characterizes the onset and progression of AD, which can be also driven by the alteration of metallostasis (metal homeostasis) of d-block metal ions, such as copper(II) and zinc(II). The “Metal Hypothesis” in AD also concerns the effects of these metal ions on the formation and activity of Aβ fragments. Once Aβ is processed by the Aβ-degrading systems, the amyloid fragments can lose, maintain or modify the metal binding properties, unlike the full-length peptide. In addition, the physiological and/or pathological functions of the peptide fragments and their metal complexes can be different from those exerted by Aβ and its metal complex systems. We will outline the Aβ fragments detected in human fluids and tissues from both healthy and AD patients, as well as the structural and biochemical features of copper(II) and zinc(II) complexes with the naturally-occurring Aβ fragments. Then we will delve into the essential features and functionalities of the enzymatic systems involved in the clearance and degradation of Aβ and the effects of Cu2+ and Zn2+ in their activity. Finally, we will explain how we to match the cleavage sites of the Aβ-degrading enzymes to the natural-occurring cleavage sites of Aβ.