An inorganic overview of natural A beta fragments: Copper(II) and zinc(II)-mediated pathways

Overwhelming evidence clearly indicates that the abnormal aggregation of A beta 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 A beta fragments. Once A beta is processed by the AO-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 A beta and its metal complex systems.

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 (AD) 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 A beta 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 A beta from the amyloid precursor protein (APP) have been unveiled, the mechanism involved in the control of A beta levels through enzymatic systems (UPS, lysosomes and A beta-degrading enzymes), both in vitro and in vivo, is underexplored.