Structure and Synaptic Function of Metal Binding to the Amyloid Precursor Protein and its Proteolytic Fragments

Abstract

Alzheimer’s disease (AD) is ultimately linked to the amyloid precursor protein (APP). However, current research reveals an important synaptic function of APP and APP-like proteins (APLP1 and 2). In this context various neurotrophic and neuroprotective functions have been reported for the APP proteolytic fragments sAPPα, sAPPβ and the monomeric amyloid-beta peptide (Aβ). APP is a metalloprotein and binds copper and zinc ions. Synaptic activity correlates with a release of these ions into the synaptic cleft and dysregulation of their homeostasis is linked to different neurodegenerative diseases. Metal binding to APP or its fragments affects its structure and its proteolytic cleavage and therefore its physiological function at the synapse. Here, we summarize the current data supporting this hypothesis and provide a model of how these different mechanisms might be intertwined with each other.

A Trishistidine Pseudopeptide with Ability to Remove Both CuΙ and CuΙΙ from the Amyloid‐β Peptide and to Stop the Associated ROS Formation

“…[8] While AD is a multi-factorial disease, involving many biological actors and complex interactions between them (Aβ and Tau protein, secretases responsible of the production of the (non-)amyloidogenic forms of the Aβ, acetylcholine esterase…. ),[9] CuAβ associated ROS over-production is recognized as a key event. [10] Copper ions thus remain a pertinent target for a therapeutic approach,[3d, 5a, 10a, 11] although the first clinical trials along this approach failed to benefit patients.…”

“…[3d, 12] Targeting Cu ions requires well-defined coordination based approaches and ligand design that is, in general, difficult to include in multi-targeted drug in a first-line strategy. [9a] Hence, we designed the chelating moiety of a drug candidate that could be further implemented towards a multi-targeted purpose.…”

“…[3d, 9a, 11, 13] for recent reviews), including with peptide-based ligands. [14] Only few studies have focused on Cu i synthetic chelators,[15] based on previous results using naturally occurring Cu i proteins.…”

“…[20] In addition, although the redox cycle between Cu i and Cu ii is the pre-requisite for ROS production implying that both redox states may be present, one redox state may be largely predominant and it is not known yet which one it is. Thus targeting either Cu ii or Cu i might be a uncertain approach ; chelators are, in general, specific for one given redox state,[3d, 9a, 11, 13, 15a] because Cu ii and Cu i coordination requirements are very different[21] (distorted square-planar, with N/O ligands for Cu ii and tetrahedral with N,S ligands for Cu i ). Hence, the risk is to miss the good target since it has for instance been shown that although being able to remove Cu ii from Aβ and being redox inert, tetraazamacrocycle ligands failed in stopping CuAβ induced ROS production.…”

Copper and zinc ions govern the trans‐directed dimerization of APP family members in multiple ways

“…), with low nanomolar binding affinities (Wild et al . ). Zinc can bind to two distinct sites in the E2 domain, one encompassing three of the histidine residues that are also involved in copper binding (H382, H432, H436; K d = 4 μM) (Dahms et al .…”