Antiamyloidogenic Activity of Aβ42‐Binding Peptoid in Modulating Amyloid Oligomerization

The oligomerization and aggregation of amyloid β (Aβ) play central role in the pathogenesis of Alzheimer's disease (AD). Molecular binding agents for modulating the formation of Aβ oligomers and fibrils have promising application potential in AD therapies. By screening a peptoid library using surface plasmon resonance imaging, amyloid inhibitory peptoid 1 (AIP1) that has high affinity to Aβ42 is identified. AIP1 is demonstrated to inhibit Aβ42 oligomerization and fibrillation and to rescue Aβ42‐induced cytotoxicity through decreasing the content of Aβ42 oligomers that is related to cell membrane permeability. Molecular docking suggests that the binding sites of AIP1 may be at the N‐terminus of Aβ42. The blood‐brain barrier (BBB) permeability of AIP1 using an in vitro BBB model is also revealed. This work provides a strategy for the design and development of peptoid‐based antiamyloidogenic agents. The obtained amyloid inhibitory peptoid shows prospects in the therapeutic application in AD.     

Detection of β‐Amyloid by Sialic Acid Coated Bovine Serum Albumin Magnetic Nanoparticles in a Mouse Model of Alzheimer's Disease

The accumulation and formation of β‐amyloid (Aβ) plaques in the brain are distinctive pathological hallmarks of Alzheimer's disease (AD). Designing nanoparticle (NP) contrast agents capable of binding with Aβ highly selectively can potentially facilitate early detection of AD. However, a significant obstacle is the blood brain barrier (BBB), which can preclude the entrance of NPs into the brain for Aβ binding. In this work, bovine serum albumin (BSA) coated NPs are decorated with sialic acid (NP‐BSA_x‐Sia) to overcome the challenges in Aβ imaging in vivo. The NP‐BSA_x‐Sia is biocompatible with high magnetic relaxivities, suggesting that they are suitable contrast agents for magnetic resonance imaging (MRI). The NP‐BSA_x‐Sia binds with Aβ in a sialic acid dependent manner with high selectivities toward Aβ deposited on brains and cross the BBB in an in vitro model. The abilities of these NPs to detect Aβ in vivo in human AD transgenic mice by MRI are evaluated without the need to coinject mannitol to increase BBB permeability. T₂*‐weighted MRI shows that Aβ plaques in mouse brains can be detected as aided by NP‐BSA_x‐Sia, which is confirmed by histological analysis. Thus, NP‐BSA_x‐Sia is a promising new tool for noninvasive in vivo detection of Aβ plaques.     

Adsorption of amyloid beta (1-40) peptide at phospholipid monolayers

The folding of amyloid beta (1-40) peptide into beta-sheet-containing fibrils is thought to play a causative role in Alzheimer's disease. Because of its amphiphilic character, the peptide can interact with phospholipid membranes. Langmuir monolayers of negatively charged DPPS, DPPG, and DMPG, and also of zwitterionic DPPC and DMPC, have been used to study the influence of the peptide on the lipid packing and, vice versa, the influence of phospholipid monolayers on the peptide secondary structure by infrared reflection absorption spectroscopy and grazing incidence X-ray diffraction. The peptide adsorbs at the air/water (buffer) interface, and also inserts into uncompressed phospholipid monolayers. When adsorbed at the interface, the peptide adopts a beta-sheet conformation, with the long axis of these beta-sheets oriented almost parallel to the surface. If the lipid exhibits a condensed monolayer phase, then compression of the complex monolayer with the inserted peptide leads to the squeezing out of the peptide at higher surface pressures (above 30 mN m(-1)). The peptide desorbs completely from zwitterionic monolayers and negatively charged DPPG and DPPS monolayers on buffer, but remains adsorbed in the beta-sheet conformation at negatively charged monolayers on water. This can be explained in terms of electrostatic interactions with the lipid head groups. It also remains adsorbed at, or penetrating into, disordered anionic monolayers on buffer. Additionally, the peptide does not influence the condensed monolayer structure at physiological pH and modest ionic strength.     

Calcium Dyshomeostasis in Alzheimer’s Disease Pathogenesis

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that is characterized by amyloid β-protein deposition in senile plaques, neurofibrillary tangles consisting of abnormally phosphorylated tau protein, and neuronal loss leading to cognitive decline and dementia. Despite extensive research, the exact mechanisms underlying AD remain unknown and effective treatment is not available. Many hypotheses have been proposed to explain AD pathophysiology; however, there is general consensus that the abnormal aggregation of the amyloid β peptide (Aβ) is the initial event triggering a pathogenic cascade of degenerating events in cholinergic neurons. The dysregulation of calcium homeostasis has been studied considerably to clarify the mechanisms of neurodegeneration induced by Aβ. Intracellular calcium acts as a second messenger and plays a key role in the regulation of neuronal functions, such as neural growth and differentiation, action potential, and synaptic plasticity. The calcium hypothesis of AD posits that activation of the amyloidogenic pathway affects neuronal Ca²⁺ homeostasis and the mechanisms responsible for learning and memory. Aβ can disrupt Ca²⁺ signaling through several mechanisms, by increasing the influx of Ca²⁺ from the extracellular space and by activating its release from intracellular stores. Here, we review the different molecular mechanisms and receptors involved in calcium dysregulation in AD and possible therapeutic strategies for improving the treatment.     

Conformational Transitions of the Amyloid-β Peptide Upon Copper(II) Binding and pH Changes

Amyloid-β (Aβ) is a natively unfolded peptide found in all Alzheimer's disease patients as the major component of fibrillar plaques, which are recognized as an important pathological hallmark in Alzheimer's disease. The binding of copper to Aβ increases its neurotoxicity, as Cu²⁺ causes Aβ to become redox active and decreases the lag time associated with Aβ aggregation. In addition, the pH is a major factor that influences both the Aβ aggregation rates and Cu²⁺ binding. Hamiltonian replica exchange molecular dynamics (H-REMD) simulations enable atomistic insights into the effects of pH and Cu²⁺ complexation on the structure and dynamics of Aβ. To study the Aβ_1–42/Cu²⁺ complex, we have developed new force-field parameters for the divalent copper ion ligated by the two histidine residues, His6 and His13, as well as the amine and carbonyl groups of Asp1, in a distorted square-planar geometry. Our comparative simulations reveal that both Cu²⁺ binding and a low pH-mimicking acidosis, linked to inflammatory processes in vivo, accelerate the formation of β-strands in Aβ_1–42 and lead to the stabilization of salt bridges, previously shown to promote Aβ aggregation. The results suggest that Cu²⁺ binding and mild acidic conditions can shift the conformational equilibrium towards aggregation-prone conformers for the monomeric Aβ.     

Compilation and Analysis of Enzymes,Engineered Antibodies,and Nanoparticles Designed to Interfere with Amyloid-β Aggregation

The abnormal accumulation and aggregation of amyloid β (Aβ) is one of the key factors of the synaptic impairment in Alzheimer's disease. Biomolecules, e.g., apolipoproteins, and membrane receptors, are implicated in the aggregation and toxicity of Aβ. Engineered molecules, such as enzymes, antibodies, and nanoparticles, are designed to interfere with these processes. We compile structural information on these molecules and their essential roles in the complex processes of aggregation, disaggregation, degradation, clearance, and inhibition of Aβ. The interactions between Aβ and its partners have no obvious emerging commonalities. One exception is the recognition of the N-terminal region of Aβ peptides by antibody heavy and light chains, which are facilitated by cooperative interaction not observed in other Aβ-peptide molecules. Overall, the emerging picture charts a diverse, to date unexplored, landscape and serves as the first-of-its-kind partner- and scenario-specific analysis.     

Nanoscale Discrimination between Toxic and Nontoxic Protein Misfolded Oligomers with Tip‐Enhanced Raman Spectroscopy

Highly toxic protein misfolded oligomers associated with neurological disorders such as Alzheimer's and Parkinson's diseases are nowadays considered primarily responsible for promoting synaptic failure and neuronal death. Unraveling the relationship between structure and neurotoxicity of protein oligomers appears pivotal in understanding the causes of the pathological process, as well as in designing novel diagnostic and therapeutic strategies tuned toward the earliest and presymptomatic stages of the disease. Here, it is benefited from tip‐enhanced Raman spectroscopy (TERS) as a surface‐sensitive tool with spatial resolution on the nanoscale, to inspect the spatial organization and surface character of individual protein oligomers from two samples formed by the same polypeptide sequence and different toxicity levels. TERS provides direct assignment of specific amino acid residues that are exposed to a large extent on the surface of toxic species and buried in nontoxic oligomers. These residues, thanks to their outward disposition, might represent structural factors driving the pathogenic behavior exhibited by protein misfolded oligomers, including affecting cell membrane integrity and specific signaling pathways in neurodegenerative conditions.     

Recent advances in nanofibrous assemblies based on β‐sheet‐forming peptides for biomedical applications

Amyloid fibrils are supramolecular polymers with β‐sheet‐rich structures formed by polymerization of protein/peptide with intermolecular interaction. Amyloid fibrils have been miscast as toxic villains since they have historically been studied as pathogens associated with serious diseases, including Alzheimer's and Parkinson's disease. However, recent studies on their toxicity and formation mechanism and discovery of their functionality in nature correct the misconception and strongly facilitate the possible use of β‐sheet‐forming peptides in designing novel nanomaterials. Self‐assembly based on β‐sheet‐forming peptides can provide highly ordered nanostructures under certain conditions. Therefore, ingenious design of the building block peptides allows the construction of nano‐assemblies, which contain large quantities of bio‐functional molecules, including drugs and bioactive peptides, and exhibit unique properties, such as assembly or disassembly in response to external stimulus or specific molecules. These properties provide a novel strategy for the creation of innovative nanomaterials, especially for biomedical applications. Here, we describe recent progress in the biomedical application of fibrous assemblies based on β‐sheet‐forming peptides, such as the suppression of aberrant protein aggregation, controlled release, tissue engineering and other applications. This review focuses not only on the function of the nanofibrous assemblies but also on the functions of component molecules, namely amyloidogenic peptides. © 2016 Society of Chemical Industry