Insight into Cross-Amyloid Interactions and Morphologies: Molecular Dynamics Simulations of Model Peptide Fragments of Amyloid-β (Aβ16-22) and Islet Amyloid Polypeptide (IAPP20-29)

Amyloid-beta (Aβ) and islet amyloid polypeptide (IAPP) are small peptides, classified as amyloids, that have the potential to self-assemble and form cytotoxic species, such as small soluble oligomers and large insoluble fibrils. The formation of Aβ aggregates facilitates the progression of Alzheimer’s disease (AD), while IAPP aggregates induce pancreatic β-cell apoptosis, leading to exacerbation of Type 2 diabetes (T2D). Cross-amyloid interactions between Aβ and IAPP have been described both in vivo and in vitro, implying the role of Aβ or IAPP as modulators of cytotoxic self-aggregation of each peptide, and suggesting that Aβ-IAPP interactions are a potential molecular link between AD and T2D. Using molecular dynamics simulations, “hot spot” regions of the two peptides were studied to understand the formation of hexamers in a heterogenous and homogenous peptide-containing environment. Systems of only Aβ(16-22) peptides formed antiparallel, β-barrel-like structures, while systems of only IAPP(20-29) peptides formed stacked, parallel beta strands and had relatively unstable aggregation structures after 2 μs of simulation time. Systems containing both Aβ and IAPP (1:1 ratio) hexamers showed antiparallel, β-barrel-like structures, with an interdigitated arrangement of Aβ(16-22) and IAPP(20-29). These β-barrel structures have features of cytotoxic amyloid species identified in previous literature. Ultimately, this work seeks to provide atomistic insight into both the mechanism behind cross-amyloid interactions and structural morphologies of these toxic amyloid species.Statement of SignificanceMolecular knowledge, biophysical characterization, structural morphologies, and formation pathways of amyloid oligomers - specifically low-molecular weight, cross-amyloid oligomers - remain preliminary and undefined. Characterizing interactions between homogenous and heterogenous amyloid oligomers is of great interest given that certain oligomer morphologies contribute to cytotoxicity, eventually resulting in comorbid diseases such as Alzheimer’s disease (AD) and Type 2 Diabetes Mellitus (T2DM). Utilizing model systems (e.g., fragments of full-length peptides) and molecular dynamics (MD) simulations to probe the biophysical underpinnings of cross-amyloid oligomer structures is the first step in understanding the dynamics, stability, and potential modes of cytotoxicity of these species, providing important insights into targetable biomolecular structures.

A rare natural lipid induces neuroglobin expression to prevent amyloid oligomers toxicity and retinal neurodegeneration.

Most neurodegenerative diseases such as Alzheimer's disease are proteinopathies linked to the toxicity of amyloid oligomers. Treatments to delay or cure these diseases are lacking. Using budding yeast, we report that the natural lipid tripentadecanoin induces expression of the nitric oxide oxidoreductase Yhb1 to prevent the formation of protein aggregates during aging and extends replicative lifespan. In mammals, tripentadecanoin induces expression of the Yhb1 orthologue, neuroglobin, to protect neurons against amyloid toxicity. Tripentadecanoin also rescues photoreceptors in a mouse model of retinal degeneration and retinal ganglion cells in a Rhesus monkey model of optic atrophy. Together, we propose that tripentadecanoin affects p-bodies to induce neuroglobin expression and offers a potential treatment for proteinopathies and retinal neurodegeneration.

An Unbalanced Synaptic Transmission: Cause or Consequence of the Amyloid Oligomers Neurotoxicity?

Amyloid-β (Aβ) 1-40 and 1-42 peptides are key mediators of synaptic and cognitive dysfunction in Alzheimer’s disease (AD). Whereas in AD, Aβ is found to act as a pro-epileptogenic factor even before plaque formation, amyloid pathology has been detected among patients with epilepsy with increased risk of developing AD. Among Aβ aggregated species, soluble oligomers are suggested to be responsible for most of Aβ’s toxic effects. Aβ oligomers exert extracellular and intracellular toxicity through different mechanisms, including interaction with membrane receptors and the formation of ion-permeable channels in cellular membranes. These damages, linked to an unbalance between excitatory and inhibitory neurotransmission, often result in neuronal hyperexcitability and neural circuit dysfunction, which in turn increase Aβ deposition and facilitate neurodegeneration, resulting in an Aβ-driven vicious loop. In this review, we summarize the most representative literature on the effects that oligomeric Aβ induces on synaptic dysfunction and network disorganization.

Extract from the Marine Seaweed Padina pavonica Protects Mitochondrial Biomembranes from Damage by Amyloidogenic Peptides

The identification of compounds which protect the double-membrane of mitochondrial organelles from disruption by toxic confomers of amyloid proteins may offer a therapeutic strategy to combat human neurodegenerative diseases. Here, we exploited an extract from the marine brown seaweed Padina pavonica (PPE) as a vital source of natural bioactive compounds to protect mitochondrial membranes against insult by oligomeric aggregates of the amyloidogenic proteins amyloid-β (Aβ), α-synuclein (α-syn) and tau, which are currently considered to be major targets for drug discovery in Alzheimer’s disease (AD) and Parkinson’s disease (PD). We show that PPE manifested a significant inhibitory effect against swelling of isolated mitochondria exposed to the amyloid oligomers, and attenuated the release of cytochrome c from the mitochondria. Using cardiolipin-enriched synthetic lipid membranes, we also show that dye leakage from fluorophore-loaded vesicles and formation of channel-like pores in planar bilayer membranes are largely prevented by incubating the oligomeric aggregates with PPE. Lastly, we demonstrate that PPE curtails the ability of Aβ42 and α-syn monomers to self-assemble into larger β-aggregate structures, as well as potently disrupts their respective amyloid fibrils. In conclusion, the mito-protective and anti-aggregator biological activities of Padina pavonica extract may be of therapeutic value in neurodegenerative proteinopathies, such as AD and PD.