The amyloid-β oligomer (AβO) hypothesis was introduced in 1998. It proposed that the brain damage leading to Alzheimer's disease (AD) was instigated by soluble, ligand-like AβOs. This hypothesis was based on the discovery that fibril-free synthetic preparations of AβOs were potent CNS neurotoxins that rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998). The mechanism was attributed to disrupted signaling involving the tyrosine-protein kinase Fyn, mediated by an unknown toxin receptor. Over 4,000 articles concerning AβOs have been published since then, including more than 400 reviews. AβOs have been shown to accumulate in an AD-dependent manner in human and animal model brain tissue and, experimentally, to impair learning and memory and instigate major facets of AD neuropathology, including tau pathology, synapse deterioration and loss, inflammation, and oxidative damage. As reviewed by Hayden and Teplow in 2013, the AβO hypothesis "has all but supplanted the amyloid cascade." Despite the emerging understanding of the role played by AβOs in AD pathogenesis, AβOs have not yet received the clinical attention given to amyloid plaques, which have been at the core of major attempts at therapeutics and diagnostics but are no longer regarded as the most pathogenic form of Aβ. However, if the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease modifying therapy can be envisioned. Ensuring that lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term.

The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade

A major feature of Alzheimer's disease (AD) pathology is the plaque composed of aggregated amyloid-β (Aβ) peptide. Although these plaques may have harmful properties, there is much evidence to implicate soluble oligomeric Aβ as the primary noxious form. Aβ oligomers can be generated both extracellularly and intracellularly. Aβ is toxic to neurons in a myriad of ways. It can cause pore formation resulting in the leakage of ions, disruption of cellular calcium balance, and loss of membrane potential. It can promote apoptosis, cause synaptic loss, and disrupt the cytoskeleton. Current treatments for AD are limited and palliative. Much research and effort is being devoted to reducing Aβ production as an approach to slowing or preventing the development of AD. Aβ formation results from the amyloidogenic cleavage of human amyloid precursor protein (APP). Reconfiguring this process to disfavor amyloid generation might be possible through the reduction of APP or inhibition of enzymes that convert the precursor protein to amyloid.

Amyloid toxicity in Alzheimer's disease.

In conventional polymer materials, mechanical performance is traditionally engineered via material structure, using motifs such as polymer molecular weight, polymer branching, or copolymer-block design1. Here, by means of a model system of 4-arm poly(ethylene glycol) hydrogels crosslinked with multiple, kinetically distinct dynamic metal-ligand coordinate complexes, we show that polymer materials with decoupled spatial structure and mechanical performance can be designed. By tuning the relative concentration of two types of metal-ligand crosslinks, we demonstrate control over the material’s mechanical hierarchy of energy-dissipating modes under dynamic mechanical loading, and therefore the ability to engineer a priori the viscoelastic properties of these materials by controlling the types of crosslinks rather than by modifying the polymer itself. This strategy to decouple material mechanics from structure may inform the design of soft materials for use in complex mechanical environments.

Control of hierarchical polymer mechanics with bioinspired metal-coordination dynamics

https://minerva-access.unimelb.edu.au/bitstream/handle/11343/274479/S0021-9258(20)00095-2 pdf.pdf

The essential elements of Alzheimer's disease.

Transition-metal coordination complexes are emerging as a broad class of supramolecular crosslinks that can be used to engineer the mechanical properties of advanced structural materials Unlike conventional covalent bonds, metal-coordination bonds have the capacity to reform after rupture, thereby enabling dynamic, tunable and reversible (self-healing) mechanical properties Several biological organisms, such as marine mussels, have been found to take advantage of these unique properties of metal-coordinate complexes in the assembly of load-bearing materials for complex extraorganismal functions Accordingly, efforts to integrate metal-coordinate crosslinking in bioinspired synthetic protein and polymer hydrogels are an increasingly active area of research However, a deeper understanding of how metal-coordination bonds affect bulk mechanical properties is still missing, rendering predicting the mechanical properties of metal-coordinated materials challenging In this Review, we survey recent advances and open questions in our understanding of how chemical properties of metal-coordinate complexes influence multiscale mechanical behaviour, with the aim of presenting metal-coordination bonding as a rich, inorganic crosslinking chemistry tool We also review applications of metal-coordinate crosslinking in the design of novel materials with tunable mechanical properties, ranging from tough gels to soft robots These applications highlight the opportunities arising from the integration of this class of load-bearing crosslinks in structural materials design The reversibility of transition-metal coordination bonds affords broad control over the structural dynamics of materials This Review surveys the design principles underlying the utilization of this dynamic crosslink chemistry to engineer tunable mechanical properties in biological materials and protein and polymer hydrogels

Transition-metal coordinate bonds for bioinspired macromolecules with tunable mechanical properties

https://minerva-access.unimelb.edu.au/bitstream/handle/11343/112615/J. Biol. Chem.-2016-Gunn-6134-45 Final Published.pdf

Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

Histidine functional block copolymers are thermally self‐assembled into polymer micelles with poly‐N‐isopropylacrylamide in the core and the histidine functionality in the corona. The thermally induced self‐assemblies are reversible until treated with Cu2+ ions at 50 °C. Upon treatment with 0.5 equivalents of Cu2+ relative to the histidine moieties, metal‐ion coordination locks the self‐assemblies. The self‐assembly behavior of histidine functional block copolymers is explored at different values of pH using DLS and 1H NMR. Metal‐ion coordination locking of the histidine functional micelles is also explored at different pH values, with stable micelles forming at pH 9, observed by DLS and imaged by atomic force microscopy. The thermal self‐assembly of glycine functional block copolymers at pH 5, 7, and 9 is similar to the histidine functional materials; however, the self‐assemblies do not become stable after the addition of Cu2+, indicating that the imidazole plays a crucial role in metal‐ion coordination that locks the micelles. The reversibility of the histidine‐copper complex locking mechanism is demonstrated by the addition of acid to protonate the imidazole and destabilize the polymer self‐assemblies.

/pdf/temperature-induced-self-assembly-and-metal-ion-nvrdy3asln.pdf

Temperature‐induced self‐assembly and metal‐ion stabilization of histidine functional block copolymers

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Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

Temperature‐induced self‐assembly and metal‐ion stabilization of histidine functional block copolymers