Amyloidosis is a deleterious condition caused by abnormal amyloid fibril build-up in living tissues. To date, 42 proteins that are linked to amyloid fibrils have been discovered. Amyloid fibril structure variation can affect the severity, progression rate, or clinical symptoms of amyloidosis. Since amyloid fibril build-up is the primary pathological basis for various neurodegenerative illnesses, characterization of these deadly proteins, particularly utilising optical techniques have been a focus. Spectroscopy techniques provide significant non-invasive platforms for the investigation of the structure and conformation of amyloid fibrils, offering a wide spectrum of analyses ranging from nanometric to micrometric size scales. Even though this area of study has been intensively explored, there still remain aspects of amyloid fibrillization that are not fully known, a matter hindering progress in treating and curing amyloidosis. This review aims to provide recent updates and comprehensive information on optical techniques for metabolic and proteomic characterization of β-pleated amyloid fibrils found in human tissue with thorough literature analysis of publications. Raman spectroscopy and SAXS are well established experimental methods for study of structural properties of biomaterials. With suitable models, they offer extended information for valid proteomic analysis under physiologically relevant conditions. This review points to evidence that despite limitations, these techniques are able to provide for the necessary output and proteomics indication in order to extrapolate the aetiology of amyloid fibrils for reliable diagnostic purposes. Our metabolic database may also contribute to elucidating the nature and function of the amyloid proteome in development and clearance of amyloid diseases.
Amyloid fibers are classified as a new generation of tunable bionanomaterials that exhibit new functions related to their distinctive characteristics, such as their universality, tunability, and stiffness. Here, we introduce the catalytic residues of serine protease into a peptide catalyst (PC) via an enzyme-mimic approach. The rational design of a repeating pattern of polar and nonpolar amino acids favors the conversion of the peptides into amyloid-like fibrils via self-assembly. Distinct fibrous morphologies have been observed at different pH values and temperatures, which indicates that different fibril packing schemes can be designed; hence, fibrillar peptides can be used to generate efficient artificial catalysts for amidolytic activities at mild pH values. The results of atomic force microscopy, Raman spectroscopy, and wide-angle X-ray scattering analyses are used to discuss and compare the fibril structure of a fibrillar PC with its amidolytic activity. The pH of the fibrillation reaction crucially affects the pKa of the side chains of the catalytic triads and is important for stable fibril formation. Temperature is another important parameter that controls the self-assembly of peptides into highly stacked and laminated morphologies. The morphology and stability of fibrils are crucial and represent important factors for demonstrating the capability of the peptides to exert amidolytic activity. The observed amidolytic activity of PC4, one of the PCs, was validated using an inhibition assay, which revealed that PC4 can perform enzyme-like amidolytic catalysis. These results provide insights into the potential use of designed peptides in the generation of efficient artificial enzymes.
In this investigation, a new design based on a PANDA ring resonator as an optical trapping tool for tangle protein, molecular motor storage, and delivery is proposed. The optical vortices are generated and the trapping mechanism is controlled in the same way as the conventional optical tweezers. The trapping force is produced by a combination of the gradient field and scattering photons. The required molecular volume is trapped and moved dynamically within the molecular network. The tangle protein and molecular motor can be transported and delivered to the required destinations for Alzheimer's diagnosis by molecular buffer and bus network.
Two forms of abnormal fibrillary protein deposition are considered: amyloidosis and fibrillary (immunotactoid) glomerulonephritis. Amyloid is characterised by an antiparallel, beta-pleated configuration which imparts to it a unique apple-green birefringence after Congo red staining. Inspite of its fairly constant physical properties, the chemical composition of amyloid fibrils is amazingly diverse, encomposing AA protein, light chain fragments, transthyretin, procalcitonin, islet amyloid polypeptide, atrial natriuretic peptides, beta-amyloid protein, beta-2-microglobulin, cystatin C, gelsolin, apolipoprotein A1, lyzozyme and their mutant variants. Amyloid P component and heparan sulphate proteoglycan are ubiquitous non-fibrillary amyloid components which have significant roles in the amyloidogenetic process, as do also precursor fibril proteins. Different amyloid fibril proteins relate to different amyloidosis syndromes and different histological patterns, and provide the basis for new diagnostic approaches to this disorder. Glomerular deposits in fibrillary glomerulonephritis (FGN), although often mistaken for amyloid, differ from it in its negative Congophilia, wider fibril width and highly organised, microtubular-tactoidal appearance ultrastructurally. FGN is essentially a primary glomerulopathy resulting in progressive renal failure. Despite certain differences, intriguing similarities between both entities of fibrillary deposition pose a challenge to researchers as to the mechanisms of abnormal protein crystallization and fibril formation in tissues.
Recent evidence suggests that the formation of soluble amyloid β (Aβ) aggregates with high toxicity, such as oligomers and protofibrils, is a key event that causes Alzheimer's disease (AD). However, understanding the pathophysiological role of such soluble Aβ aggregates in the brain in vivo could be difficult due to the lack of a clinically available method to detect, visualize, and quantify soluble Aβ aggregates in the brain. We had synthesized a novel fluorinated curcumin derivative with a fixed keto form, named as Shiga-Y51, which exhibited high selectivity to Aβ oligomers in vitro. In this study, we investigated the in vivo detection of Aβ oligomers by fluorine-19 (19F) magnetic resonance imaging (MRI) using Shiga-Y51 in an APP/PS1 double transgenic mouse model of AD. Significantly high levels of 19F signals were detected in the upper forebrain region of APP/PS1 mice compared with wild-type mice. Moreover, the highest levels of Aβ oligomers were detected in the upper forebrain region of APP/PS1 mice in enzyme-linked immunosorbent assay. These findings suggested that 19F-MRI using Shiga-Y51 detected Aβ oligomers in the in vivo brain. Therefore, 19F-MRI using Shiga-Y51 with a 7 T MR scanner could be a powerful tool for imaging Aβ oligomers in the brain.
Metal ionophores are considered as potential anti-dementia agents, and some are currently undergoing clinical trials. Many metals are known to accumulate and distribute abnormally in the aging brain. Alterations in zinc metal homeostasis in the glutaminergic synapse could contribute to ageing and the pathophysiology of Alzheimer's disease (AD). The present study was designed to investigate the effect of metal ionophores on long term administration of zinc in D-galactose induced senescent mice. The ageing model was established by combined administration of zinc and D-galactose to mice for 6 weeks. A novel metal ionophore, PBT-2 was given daily to zinc-induced d-galactose senescent mice. The cognitive behaviour of mice was monitored using the Morris Water Maze. The anti-oxidant status and amyloidogenic activity in the ageing mouse was measured by determining mito-oxidative parameters and deposition of amyloid β (Aβ) in the brain. Systemic administration of both zinc and D-galactose significantly produced memory deficits, mito-oxidative damage, heightened acetylcholinesterase enzymatic activity and deposition of amyloid-β. Treatment with PBT-2 significantly improved behavioural deficits, biochemical profiles, cellular damage, and curbed the deposition of APP in zinc-induced senescent mice. These findings suggest that PBT-2, acting as a metal protein attenuating compound, may be helpful in the prevention of AD or alleviation of ageing.
Alkaloids are a class of secondary metabolites that can be derived from plants, fungi and marine sponges. They are widely known as a continuous source of medicine for the management of chronic disease including cancer, diabetes and neurodegenerative diseases. For example, galanthamine and huperzine A are alkaloid derivatives currently being used for the symptomatic management of neurodegenerative disease. The etiology of neurodegenerative diseases is polygenic and multifactorial including but not limited to inflammation, oxidative stress and protein aggregation. Therefore, natural-product-based alkaloids with polypharmacology modulation properties are potentially useful for further drug development or, to a lesser extent, as nutraceuticals to manage neurodegeneration. This review aims to discuss and summarise recent developments in relation to naturally derived alkaloids for neurodegenerative diseases.