Prominent Perspective on Existing Biological Hallmarks of Alzheimer's Disease.

Biomarkers are the most significant diagnosis tools tending towards unique approaches and solutions for the prevention and cure of Alzheimer's Disease (AD). The current report provides a clear perception of the concept of various biomarkers and their prominent features through analysis to provide a possible solution for the inhibition of events in AD. Scientists around the world truly believe that crucial hallmarks can serve as critical tools in the early diagnosis, cure, and prevention, as well as the future of medicine. The awareness and understanding of such biomarkers would provide solutions to the puzzled mechanism of this neuronal disorder. Some of the argued biomarkers in the present article are still in an experimental phase as they need to undergo specific clinical trials before they can be considered for treatment.

Propane-2-sulfonic acid octadec-9-enyl-amide, a novel PPARα/γ dual agonist, attenuates molecular pathological alterations in learning memory in AD mice.

OBJECTIVE: Previous studies have revealed that Propane-2-sulfonic acid octadec-9-enyl-amide(N15) exerts a protective role in the inflammatory response after ischemic stroke and in neuronal damage. However, little is known about N15 in Alzheimer's disease (AD). The aim of this study was to investigate the effects of N15 on AD and explore the underlying molecular mechanism. METHODS: AD mice model was established by lateral ventricular injection with Aß25-35. N15 was daily intraperitoneal administered for 28 days. Morris Water Maze was used to evaluate the neurocognitive function of the mice. The expression of PPARα/γ, brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT3), ADAM10, PS1 and BACE1 were measured by qPCR. Aß amyloid in the hippocampus was measured by Congo red assay. Toluidine blue staining was used to detect the neuronal apoptosis. Protein levels of ADAM10, PS1 and BACE1 were determined using immunoblotting. RESULTS: N15 treatment significantly reduced neurocognitive dysfunction, which also significantly activated the expression of PPARα/γ at an optimal dose of 200 mg/kg. Administration of N15 alleviated the formation of Aß amyloid in the hippocampus of AD mice, enhanced the BDNF mRNA expression, decreased the mRNA and protein levels of PS1 and BACE1, upregulated ADAM10 mRNA and protein levels. CONCLUSION: N15 exerts its neuroprotective effects through the activation of PPARα/γ and may be a potential drug for the treatment of AD.

Can Activation of Acetylcholinesterase by ß-Amyloid Peptide Decrease the Effectiveness of Cholinesterase Inhibitors?

A central event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of senile plaques composed of aggregated amyloid-ß (Aß) peptides. The main class of drugs currently used for the treatment of AD are the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. In this study, it has been shown that Aß augmented AChE activity in vitro, maximum activation of 548 ± 5% was achieved following 48 h of incubation with 10 µM of Aß1-40, leading to a 7.7-fold increase in catalytic efficiency. The observed non-competitive type of AChE activation by Aß1-40 was associated with increased Vmax and unchanged Km. Although BChE activity also increased following incubation with Aß1-40, this was less efficiently achieved as compared with AChE. Ex vivo electrophysiological experiments showed that 10 µM of Aß1-40 significantly decreased the effect of the AChE inhibitor huperzine A on the synaptic potential parameters.

Acetylcholine hydrolytic activity of fibrillated ß-amyloid (1-40) peptide.

Alzheimer's disease is characterized by the presence of senile plaques composed of ß-amyloid peptide (Aß) aggregates with toxic effects that are still not fully understood. Recently, it was discovered that Aß(1-42) fibrils possess catalytic activity on acetylcholine hydrolysis. Catalytic amyloids are an emerging and exciting field of research. In this study, we examined the catalytic activity of the fibrils formed by Aß(1-40), the most abundant Aß variant, on acetylcholine hydrolysis. Our findings reveal that Aß(1-40) fibrils exhibit moderate enzymatic activity, indicating that natural peptide aggregates could serve as biocatalysts and provide new insights into the potential role of Aß in neurological disorders.

Amyloid Fibrils of Pisum sativum L. Vicilin Inhibit Pathological Aggregation of Mammalian Proteins.

Although incurable pathologies associated with the formation of highly ordered fibrillar protein aggregates called amyloids have been known for about two centuries, functional roles of amyloids have been studied for only two decades. Recently, we identified functional amyloids in plants. These amyloids formed using garden pea Pisum sativum L. storage globulin and vicilin, accumulated during the seed maturation and resisted treatment with gastric enzymes and canning. Thus, vicilin amyloids ingested with food could interact with mammalian proteins. In this work, we analyzed the effects of vicilin amyloids on the fibril formation of proteins that form pathological amyloids. We found that vicilin amyloids inhibit the fibrillogenesis of these proteins. In particular, vicilin amyloids decrease the number and length of lysozyme amyloid fibrils; the length and width of ß-2-microglobulin fibrils; the number, length and the degree of clustering of ß-amyloid fibrils; and, finally, they change the structure and decrease the length of insulin fibrils. Such drastic influences of vicilin amyloids on the pathological amyloids' formation cause the alteration of their toxicity for mammalian cells, which decreases for all tested amyloids with the exception of insulin. Taken together, our study, for the first time, demonstrates the anti-amyloid effect of vicilin fibrils and suggests the mechanisms underlying this phenomenon.

Update on new trends and progress of natural active ingredients in the intervention of Alzheimer's disease, based on understanding of traditional Chinese and Western relevant theories: A review.

Alzheimer's disease (AD) is one of the major neurological disorders causing death in the elderly worldwide. As a neurodegenerative disease that is difficult to prevent and cure, the pathogenesis of AD is complex and there is no effective cure. A variety of natural products derived from plants have been reported to have promising anti-AD activities, including flavonoids, terpenes, phenolic acids and alkaloids, which can effectively relieve the symptoms of AD in a variety of ways. This paper mainly reviews the pharmacological activity and mechanisms of natural products against AD. Although the clinical efficacy of these plants still needs to be determined by further high-quality studies, it may also provide a basis for future researchers to study anti-AD in depth.

Single-platform, Attomolar Detection of Multiple Biomarkers by a Flexible SERS Sensor.

Early detection of Alzheimer's disease (AD) is critical for better healthcare management. Herein, we demonstrate a Surface Enhanced Raman Spectroscopy (SERS) active sensor for highly sensitive and selective detection of ß-Amyloid Peptide (Aß1-42 ), a biomarker of Alzheimer's disease. Polyacrylonitrile (PAN) nanofiber mats, containing purine-based ligand (L; 0 mg (P1 ), 50 mg (P2 ), and 100 mg (P3 )) were prepared by electrospinning followed by functionalization with silver nanoparticles (AgNPs). The fabricated SERS sensors were employed for the detection of Rhodamine 6G (Rh-6G) dye for optimization and the highest sensitivity was achieved on P3 /AgNPs SERS sensor. The P3 /AgNPs sensor was chosen for the detection of Aß1-42 and human Insulin (HI). The limit of detection (LoD) was found to be 76×10-18 M and 26×10-18 M for Aß1-42 and HI, respectively. The sensitivity achieved is one order improved for Aß1-42 and four orders for HI when compared with reported values. Also, demonstrated the selectivity of the P3 /AgNPs sensor by testing a simulated cerebrospinal fluid (CSF) and achieved easily identifiable peaks of Aß1-42 among the noise of HI and bovine serum albumin should be written before the acronym of BSA. This approach could be extended to develop ultra-sensitive flexible SERS sensors for the facile detection of multiple biomarkers on a single platform with excellent sensitivity, selectivity and stability.

Detection of ß-amyloid peptide aggregates by quartz crystal microbalance based on dual-aptamer assisted signal amplification.

ß-amyloid peptide (Aß) aggregates are regarded as a typical neuropathology hallmark for the diagnosis of Alzheimer's disease (AD). Aß40 aggregates include soluble oligomers (Aß40O) and insoluble fibrils (Aß40F). Both of them can simultaneously bind to two different kinds of its aptamer (Apt1 and Apt2). As a mass-sensitive sensing platform, quartz crystal microbalance (QCM) converts changes in mass on the Au chip surface into frequency shift. Here, a dual-aptamer assisted Aß40 aggregates assay was developed. Taking Aß40O detection as an example, Apt2 was modified on the surface of Au chip by Au-S bond. Subsequently, the solution consisted of Aß40O and gold nanoparticles-Apt1 (AuNPs-Apt1) were injected into the QCM chamber. As a result, Aß40O was specifically recognized and captured by Apt2. AuNPs-Apt1 were also combined on the surface of the Au chip because Aß40O can simultaneously bind to Apt1. Then, a significant frequency shift occurred because of the large weight of AuNPs. Similarly, this procedure can be used to detect Aß40F. This QCM biosensor was able to detect Aß40O with a range of 0.2-10 pM with a detection limit of 0.11 pM, while the linear range for Aß40F was 0.1-10 pM with a detection limit of 0.02 pM. This QCM biosensor was simple and highly sensitive, which provided a new method for Aß40 aggregates detection.

Investigation of biological activities of two cultivars of Cicer arietinum proteins mass associated with Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with some known classical factors. Cicer arietinum (Leguminosae) is a source of protein for humans and contains albumin, globulin, glutelin, and prolamin. The protein content of two cultivars of C. arietinum, Hashem and Mansour, was isolated to evaluate their inhibition activity against acetylcholinesterase (AChE), butyrylcholine esterase (BChE), and ß-amyloid peptide (ßA) aggregation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and molecular docking were also applied to evaluate the content and determine the potential of each chickpea protein to interact with AChE, respectively. Obtained data showed that proteins from both cultivars could inhibit AChE with IC50 of 17.73 (0.03) and 22.20 (0.06) µg/mL, respectively, with no activity on BChE. The 50 µg/mL protein concentration of each cultivar suppressed ßA accumulation (Mansour: 25.66% and Hashem: 21.69%) and showed biometal chelating activity. SDS-PAGE analysis revealed relatively different protein patterns, though the Mansour cultivar contained some protein bands with molecular weights of 18, 24, and 70 kDa were estimated to belong to vicilin and legumin, which were absent in the Hashem protein mass. Molecular docking showed that legumin and especially vicilin have good potential to interact with AChE. The chickpea proteins showed inhibitory activity against AChE, which might be due to the vicilin and legumin fractions. The characterization of the inhibitory effect of each protein band could be promising in finding new therapeutic peptide candidates to treat Alzheimer's in the future, although more experimental work is needed in this issue.

Exposure of combination of environmental pollutant, lead (Pb) and ß-amyloid peptides causes mitochondrial dysfunction and oxidative stress in human neuronal cells.

Exposure to the environmental pollutant lead (Pb) has been linked to Alzheimer's disease (AD), in which mitochondrial dysfunction is a pathological consequence of neuronal degeneration. The toxicity of Pb in combination with ß-amyloid peptides (1-40) and (25-35) causes selective death in neuronal cells. However, the precise mechanism through which Pb induces Alzheimer's disease, particularly mitochondrial damage, is unknown. Changes in mitochondrial mass, membrane potential, mitochondrial complex activities, mitochondrial DNA and oxidative stress were examined in neuronal cells of human origin exposed to Pb and ß-amyloid peptides (1-40) and (25-35) individually and in different combinations. The results showed depolarization of mitochondrial membrane potential, decrease in mitochondrial mass, ATP levels and mtDNA copy number in Pb and ß-amyloid peptides (1-40) and (25-35) exposed cells. Also, significant reductions in the expression of mitochondrial electron transport chain (ETC) complex proteins (ATP5A, COXIV, UQCRC2, SDHB, NDUFS3), as well as down regulation of ETC complex gene expressions such as COXIV, ATP5F1 and NDUFS3 and antioxidant gene expressions like MnSOD and Gpx4 were observed in exposed cells. Furthermore, Pb and ß-amyloid peptides exposure resulted in elevated mitochondrial malondialdehyde levels and a decrease in mitochondrial GSH levels. Our findings suggest that Pb toxicity could be one of the causative factors for the mitochondrial dysfunction and oxidative stress in Alzheimer's disease progression.

Extravaganza of Nanobiotechnology in the Diagnosis and Treatment of Dementia Patients.

Dementia impairs memory, critical thinking, and decision-making. Alzheimer's disease is caused by extracellular amyloid fibrils containing the peptide Amyloid beta (Aß) accumulating in the brain. Alzheimer's disease is the most common form of dementia. A slew of small molecule inhibitors developed over several decades has targeted dementia and related diseases. The drugs and inhibitors cannot cross the BBB due to their insurmountable nature. Many molecular nanomedicines have been developed that can cross the BBB via adsorptive-mediated transcytosis. Drug-loaded nanosized formulations, such as polymeric nanoparticles, solid lipid nano transporters, liposomes, nanoemulsions, exosomes, gold nanoparticles, and dendrimers, have a significant impact on dementia diagnosis and treatment. This review focuses on recent developments in nanotechnology-based drug delivery systems for dementia and related disorders such as Alzheimer's disease. Recent advances in nanotechnology may help overcome drug delivery limitations for dementia therapy. Nanoparticles' size, composition, and structural variety bring up new therapeutic possibilities, including treating and diagnosing neurodegenerative diseases. It is possible to enhance therapeutic effectiveness by enhancing pharmacokinetics, bioavailability, water solubility, and stability under physiological conditions while reducing adverse effects by restricting their location in healthy tissues.

Electrochemical Immunosensor for Early Detection of ß-Amyloid Alzheimer's Disease Biomarker Based on Aligned Carbon Nanotubes Gold Nanocomposites.

Beta-amyloid (ßA) peptides accompanying the physiological change in brain induce Alzheimer's disease. In this work, a highly sensitive electrochemical (EC) immunosensor platform has been developed for the quantitative detection of ßA peptides, using the gold nanoparticle functionalized chitosan-aligned carbon nanotube (CS-aCNT-Au) nanocomposites on glassy carbon electrodes (GCE). The immunosensor has been fabricated by immobilization of the anti-ßA antibody upon CS-aCNT-Au/GCE. In the CS-aCNT nanocomposite, CS has high biocompatibility. Hydroxy and amine functionalities favor the antibody immobilization and prevent the leaching of nanocomposites of the modified electrode due to the adhesive environment. Moreover, aCNT offers high conductivity, stability, and a large surface area (the calculated effective surface area of the CS-aCNT/GCE is 8.594 × 10-2 cm2). However, the incorporation of AuNPs further enhances the conductivity of the CS-aCNT-Au nanocomposite based on differential pulse voltammetry (DPV) results, and also improves the effective surface area (9.735 × 10-2 cm2). The surface morphology and electrochemical studies of the nanocomposite, as well as its modifications by the anti-ßA antibody and BSA, were carried out through field emission scanning electron microscope (FESEM), cyclic voltammetry (CV), and DPV. The quantitative immunosensing of the ßA in phosphate-buffered saline (PBS) solution is accomplished via DPV, which reveals that the immunosensor has a high sensitivity of 157.60 µA pg-1 mL cm-2 and a broad detection range of 10.0 pg mL-1-100.0 µg mL-1, with a limit of detection (LOD) of 0.87 pg mL-1. Subsequently, we detected the spiked ßA in diluted serum with a linear detection range of 10.0 pg mL-1-1.0 ng mL-1 and LOD of 0.95 pg mL-1. Moreover, a selectivity study exhibited a high affinity of immunosensors towards ßA. Thus, we propose that this highly efficient immunosensor can potentially be applied for the point-of-care (POC) sensing of ßA in clinical samples.

Intracerebroventricular administration of oxytocin and intranasal administration of the oxytocin derivative improve ß-amyloid peptide (25-35)-induced memory impairment in mice.

AIM: We previously reported that oxytocin, a peptide hormone, can reverse the ß-amyloid peptide (25-35) (Aß25-35 )-induced impairments of the murine hippocampal synaptic plasticity. In this study, we examined the effects of oxytocin on the Aß25-35 -induced impairment of cognitive behavior in murine in order to investigate the potential of oxytocin as a clinical treatment tool for Alzheimer's disease (AD). METHODS: The Y-maze and Morris water maze (MWM) tests were performed. Since the intracerebroventricular (ICV) administration is both invasive and impractical, we further utilized intranasal (IN) delivery to the brain. For this purpose, we prepared an oxytocin derivative containing cell-penetrating peptides and a penetration accelerating sequence, which was subsequently used in our IN administration experiments. RESULTS: We herein showed that the ICV administration of oxytocin in mice exerted memory-improving effects on the Aß25-35 -induced amnesia in both the Y-maze and MWM tests. The IN administration of the oxytocin derivative exhibited memory-improving effects in the Y-maze test. Moreover, we acquired evidence that the fluorescein isothiocyanate-labeled oxytocin derivative was distributed throughout the mouse brain following its IN administration. CONCLUSION: Our results suggest that the oxytocin derivative is effective for its IN delivery to the brain and may be particularly useful in the clinical treatment of cognitive impairment, such as that characterizing AD.

1-L Transcription in Alzheimer's Disease.

Alzheimer's disease is a very complex disease and better explanations and models are needed to understand how neurons are affected and microglia are activated. A new model of Alzheimer's disease is presented here, the ß-amyloid peptide is considered an important RNA recognition/binding peptide. 1-L transcription revealed compatible sequences with AAUAAA (PAS signal) and UUUC (class III ARE rich in U) in the Aß peptide, supporting the peptide-RNA regulatory model. When a hypothetical model of fibril selection with the prionic character of amyloid assemblies is added to the peptide-RNA regulatory model, the downregulation of the PI3K-Akt pathway and the upregulation of the PLC-IP3 pathway are well explained. The model explains why neurons are less protected from inflammation and why microglia are activated; why mitochondria are destabilized; why the autophagic flux is destabilized; and why the post-transcriptional attenuation of the axonal signal "noise" is interrupted. For example, the model suggests that Aß peptide may post-transcriptionally control ELAVL2 (ELAV-like RNA binding protein 2) and DCP2 (decapping mRNA protein 2), which are known to regulate RNA processing, transport, and stability.

Characterizing Heparin Tetrasaccharides Binding to Amyloid-Beta Peptide.

The aggregation of ß-amyloid peptide (Aß) is one potential cause for Alzheimer's disease (AD). Heparin can either promote or inhibit Aß aggregation. The sulfation pattern and chain size determine its binding affinity and its role. Using 2D-NMR analysis and molecular modelling, the binding motif of heparin oligoaccharides to Aß was determined to be HexA-GlcNS-IdoA2S-GlcNS6S. Iduronic acid epimerization and 6-O-sulfation are key factors for the binding affinity, while 3-O-sulfation of Arixtra (heparin pentasaccharide) is not involved in the binding to Aß. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) was used to study the glycosaminoglycan (GAG)-peptide complex and identified V12HHQKL17 as the binding site of GAG at Aß. Furthermore, an MTT assay was applied to evaluate the anti-Aß fibril formation function of heparin tetrasaccharide, and indicated that the heparin tetrasaccharide with the defined sequence represents a promising inhibitor of Aß aggregation.

Defective mitophagy and induction of apoptosis by the depleted levels of PINK1 and Parkin in Pb and ß-amyloid peptide induced toxicity.

Exposure to lead (Pb), an environmental pollutant, is closely associated with the development of neurodegenerative disorders through oxidative stress induction and alterations in mitochondrial function. Damaged mitochondria could be one of the reasons for the progression of Alzheimer's Disease (AD). Mitophagy is vital in keeping the cell healthy. To know its role in Pb-induced AD, we investigated the PINK1/Parkin dependent pathway by studying specific mitophagy marker proteins such as PINK1 and Parkin in differentiated SH-SY5Y cells. Our data have indicated a significant reduction in the levels of PINK1 and Parkin in cells exposed to Pb and ß-amyloid peptides, both Aß (25-35) and Aß (1-40) individually and in different combinations, resulting in defective mitophagy. Also, the study unravels the status of mitochondrial permeability transition pore (MPTP), mitochondrial mass, mitochondrial membrane potential (MMP) and mitochondrial ROS production in cells treated with individual and different combination of Pb and Aß peptides. An increase in mitochondrial ROS production, enhanced MPTP opening, depolarization of membrane potential and reduced mitochondrial mass in the exposed groups were observed. Also, in the present study, we found that Pb and ß-amyloid peptides could trigger apoptosis by activating the Bak protein, which releases the cytochrome c from mitochondria through MPTP that further activates the AIF (apoptosis inducing factor) and caspase-3 proteins in the cytosol. The above findings reveal the potential role of mechanisms like PINK1/Parkin mediated mitophagy and dysfunctional mitochondria mediated apoptosis in Pb induced neurotoxicity.

Mechanisms associated with the dysregulation of mitochondrial function due to lead exposure and possible implications on the development of Alzheimer's disease.

Lead (Pb) is a multimedia contaminant with various pathophysiological consequences, including cognitive decline and neural abnormalities. Recent findings have reported an association of Pb toxicity with Alzheimer's disease (AD). Studies have revealed that mitochondrial dysfunction is a pathological characteristic of AD. According to toxicology reports, Pb promotes mitochondrial oxidative stress by lowering complex III activity in the electron transport chain, boosting reactive oxygen species formation, and reducing the cell's antioxidant defence system. Here, we review recent advances in the role of mitochondria in Pb-induced AD pathology, as well as the mechanisms associated with the mitochondrial dysfunction, such as the depolarisation of the mitochondrial membrane potential, mitochondrial permeability transition pore opening; mitochondrial biogenesis, bioenergetics and mitochondrial dynamics alterations; and mitophagy and apoptosis. We also discuss possible therapeutic options for mitochondrial-targeted neurodegenerative disease (AD).

The Beneficial Role of Exercise on Treating Alzheimer's Disease by Inhibiting ß-Amyloid Peptide.

Alzheimer's disease (AD) is associated with a very large burden on global healthcare systems. Thus, it is imperative to find effective treatments of the disease. One feature of AD is the accumulation of neurotoxic ß-amyloid peptide (Aß). Aß induces multiple pathological processes that are deleterious to nerve cells. Despite the development of medications that target the reduction of Aß to treat AD, none has proven to be effective to date. Non-pharmacological interventions, such as physical exercise, are also being studied. The benefits of exercise on AD are widely recognized. Experimental and clinical studies have been performed to verify the role that exercise plays in reducing Aß deposition to alleviate AD. This paper reviewed the various mechanisms involved in the exercise-induced reduction of Aß, including the regulation of amyloid precursor protein cleaved proteases, the glymphatic system, brain-blood transport proteins, degrading enzymes and autophagy, which is beneficial to promote exercise therapy as a means of prevention and treatment of AD and indicates that exercise may provide new therapeutic targets for the treatment of AD.

Impact of age, hypercholesterolemia, and the vitamin D receptor on brain endogenous ß-amyloid peptide accumulation in mice.

Age, hypercholesterolemia, and vitamin D deficiency are risk factors that increase the brain accumulation of pathogenic ß-amyloid peptides (40 and 42), precursors leading to Alzheimer's disease (AD) in humans. The relative changes accompanying aging, high cholesterol, and/or treatment of calcitriol, active vitamin D receptor (VDR) ligand, under normal physiology are unknown. We examined these relative changes in C57BL/6 mice of ages 2, 4-8, and more than 10 months old, which were fed a normal or high fat / high cholesterol diet and treated with calcitriol, active ligand of the vitamin D receptor (0 or 2.5 µg/kg ×4, intraperitoneally, every other day to elicit cholesterol lowering in liver). Aß40 but not Aß42 accumulation in brain and lower P-glycoprotein (P-gp) and neprilysin protein expressions for Aß efflux and degradation, respectively, were found to be associated with aging. But there was no trend for BACE1 (ß-secretase 1, a cholesterol-sensitive enzyme) toward Aß synthesis with age. In response to calcitriol treatment, P-gp was elevated, mitigating partially the age-related changes. Although age-dependent decreasing trends in mRNA expression levels existed for Cyp46a1, the brain cholesterol processing enzyme, whose inhibition increases BACE1 and ApoE to facilitate microglia Aß degradation, mRNA changes for other cholesterol transporters: Acat1 and Abca1, and brain cholesterol levels remained unchanged. There was no observable change in the mRNA expression of amyloid precursor protein (APP) and the influx (RAGE) and efflux (LRP1) transporters with respect to age, diet, or calcitriol treatment. Overall, aging poses as a risk factor contributing to Aß accumulation in brain, and VDR-mediated P-gp activation partially alleviates the outcome.

Exploring amyloid oligomers with peptide model systems.

The assembly of amyloidogenic peptides and proteins, such as the ß-amyloid peptide, α-synuclein, huntingtin, tau, and islet amyloid polypeptide, into amyloid fibrils and oligomers is directly linked to amyloid diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases, frontotemporal dementias, and type II diabetes. Although amyloid oligomers have emerged as especially important in amyloid diseases, high-resolution structures of the oligomers formed by full-length amyloidogenic peptides and proteins have remained elusive. Investigations of oligomers assembled from fragments or stabilized ß-hairpin segments of amyloidogenic peptides and proteins have allowed investigators to illuminate some of the structural, biophysical, and biological properties of amyloid oligomers. Here, we summarize recent advances in the application of these peptide model systems to investigate and understand the structures, biological properties, and biophysical properties of amyloid oligomers.