Chemically Driven Clearance of Amyloid Aggregates by Polyfunctionalized Furo[2,3-b:4,5-b']dipyridine-Chalcone Hybrids to Ameliorate Memory in an Alzheimer Mouse Model.

The aberrant assembly of amyloid-ß (Aß) is implicated in Alzheimer's disease (AD). Recent clinical outcomes of Aß-targeted immunotherapy reinforce the notion that clearing Aß burden is a potential therapeutic approach for AD. Herein, to develop drug candidates for chemically driven clearance of Aß aggregates, we synthesized 51 novel polyfunctionalized furo[2,3-b:4,5-b']dipyridine-chalcone hybrid compounds. After conducting two types of cell-free anti-Aß functional assays, Aß aggregation prevention and Aß aggregate clearance, we selected YIAD-0336, (E)-8-((1H-pyrrol-2-yl)methylene)-10-(4-chlorophenyl)-2,4-dimethyl-7,8-dihydropyrido[3',2':4,5]furo[3,2-b]quinolin-9(6H)-one, for further in vivo investigations. As YIAD-0336 exhibited a low blood-brain barrier penetration profile, it was injected along with aggregated Aß directly into the intracerebroventricular region of ICR mice and ameliorated spatial memory in Y-maze tests. Next, YIAD-0336 was orally administered to 5XFAD transgenic mice with intravenous injections of mannitol, and YIAD-0336 significantly removed Aß plaques from the brains of 5XFAD mice. Collectively, YIAD-0336 dissociated toxic aggregates in the mouse brain and hence alleviated cognitive deterioration. Our findings indicate that chemically driven clearance of Aß aggregates is a promising therapeutic approach for AD.

Comparison of the acid suppression effects between low-dose esomeprazole and famotidine in healthy subjects.

OBJECTIVE: Famotidine, an H2 receptor antagonist (H2RA), is mainly prescribed to alleviate the early symptoms of gastritis. Our aim was to explore the possibilities of low-dose esomeprazole as a treatment of gastritis as well as the pharmacodynamic (PD) properties of esomeprazole and famotidine. MATERIALS AND METHODS: A randomized, multiple-dose, 6-sequence, 3-period crossover study was conducted with a 7-day washout between periods. For each period, the subjects were administered one dose of esomeprazole 10 mg or famotidine 20 mg or esomeprazole 20 mg each day. To evaluate the PDs, the 24-hour gastric pH was recorded after single and multiple doses. The mean percentage of time during which the gastric pH was above 4 was evaluated for PD assessment. To confirm the pharmacokinetic (PK) characteristics of esomeprazole, blood was collected for up to 24 hours after multiple doses. RESULTS: 26 subjects completed the study. Following the multiple doses of esomeprazole 10 mg, esomeprazole 20 mg, and famotidine 20 mg, the mean percentages of time during which the gastric pH was above 4 over the course of 24 hour were 35.77 ± 19.56%, 53.75 ± 20.55%, and 24.48 ± 17.36%, respectively. After multiple doses, the time of peak plasma concentration at steady state (tmax,ss) was 1.00 and 1.25 hours for 10 and 20 mg of esomeprazole, respectively. The geometric mean ratio and its 90% confidence interval of area under the plasma drug concentration-time curve in steady state (AUCT,ss) and maximum concentration of drug in plasma in steady state (Cmax,ss) for esomeprazole 10 mg compared to 20 mg were 0.3654 (0.3381 - 0.3948) and 0.5066 (0.4601 - 0.5579), respectively. CONCLUSION: The PD parameters of esomeprazole 10 mg were comparable to those of famotidine after multiple doses. These findings provide support for further evaluating the use of 10 mg of esomeprazole as a treatment option for gastritis.

Glycosylated and Succinylated Macrocyclic Lactones with Amyloid-ß-Aggregation-Regulating Activity from a Marine Bacillus sp.

Two new glycosylated and succinylated macrocyclic lactones, succinyl glyco-oxydifficidin (1) and succinyl macrolactin O (2), were isolated from a Bacillus strain collected from an intertidal mudflat on Anmyeon Island in Korea. The planar structures of 1 and 2 were proposed using mass spectrometric analysis and NMR spectroscopic data. The absolute configurations of 1 and 2 were determined by optical rotation, J-based configuration analysis, chemical derivatizations, including the modified Mosher's method, and quantum-mechanics-based calculation. Biological evaluation of 1 and 2 revealed that succinyl glyco-oxydifficidin (1) inhibited/dissociated amyloid ß (Aß) aggregation, whereas succinyl macrolactin O (2) inhibited Aß aggregation, indicating their therapeutic potential for disassembling and removing Aß aggregation.

Amyloid Against Amyloid: Dimeric Amyloid Fragment Ameliorates Cognitive Impairments by Direct Clearance of Oligomers and Plaques.

Amyloid-ß (Aß) in the form of neurotoxic aggregates is regarded as the main pathological initiator and key therapeutic target of Alzheimer's disease. However, anti-Aß drug development has been impeded by the lack of a target needed for structure-based drug design and low permeability of the blood-brain barrier (BBB). An attractive therapeutic strategy is the development of amyloid-based anti-Aß peptidomimetics that exploit the self-assembling nature of Aß and penetrate the BBB. Herein, we designed a dimeric peptide drug candidate based on the N-terminal fragment of Aß, DAB, found to cross the BBB and solubilize Aß oligomers and fibrils. Administration of DAB reduced amyloid burden in 5XFAD mice, and downregulated neuroinflammation and prevented memory impairment in the Y-maze test. Peptide mapping assays and molecular docking studies were utilized to elucidate DAB-Aß interaction. To further understand the active regions of DAB, we assessed the dissociative activity of DAB with sequence modifications.

Glucosylceramide synthase regulates adipo-osteogenic differentiation through synergistic activation of PPARγ with GlcCer.

Dysregulation of the adipo-osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and osteoporosis. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation; however, the detailed underlying mechanisms are largely unknown. Here, we demonstrate that glucosylceramide (GlcCer) and its synthase, glucosylceramide synthase (GCS), are key determinants of MSC differentiation into adipocytes or osteoblasts. GCS expression was increased during adipogenesis and decreased during osteogenesis. Targeting GCS using RNA interference or a chemical inhibitor enhanced osteogenesis and inhibited adipogenesis by controlling the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ). Treatment with GlcCer sufficiently rescued adipogenesis and inhibited osteogenesis in GCS knockdown MSCs. Mechanistically, GlcCer interacted directly with PPARγ through A/B domain and synergistically enhanced rosiglitazone-induced PPARγ activation without changing PPARγ expression, thereby treatment with exogenous GlcCer increased adipogenesis and inhibited osteogenesis. Animal studies demonstrated that inhibiting GCS reduced adipocyte formation in white adipose tissues under normal chow diet and high-fat diet feeding and accelerated bone repair in a calvarial defect model. Taken together, our findings identify a novel lipid metabolic regulator for the control of MSC differentiation and may have important therapeutic implications.

O-GlcNAcylation regulates dopamine neuron function, survival and degeneration in Parkinson disease.

The dopamine system in the midbrain is essential for volitional movement, action selection, and reward-related learning. Despite its versatile roles, it contains only a small set of neurons in the brainstem. These dopamine neurons are especially susceptible to Parkinson's disease and prematurely degenerate in the course of disease progression, while the discovery of new therapeutic interventions has been disappointingly unsuccessful. Here, we show that O-GlcNAcylation, an essential post-translational modification in various types of cells, is critical for the physiological function and survival of dopamine neurons. Bidirectional modulation of O-GlcNAcylation importantly regulates dopamine neurons at the molecular, synaptic, cellular, and behavioural levels. Remarkably, genetic and pharmacological upregulation of O-GlcNAcylation mitigates neurodegeneration, synaptic impairments, and motor deficits in an animal model of Parkinson's disease. These findings provide insights into the functional importance of O-GlcNAcylation in the dopamine system, which may be utilized to protect dopamine neurons against Parkinson's disease pathology.

The Role of Phospholipase C in GABAergic Inhibition and Its Relevance to Epilepsy.

Epilepsy is characterized by recurrent seizures due to abnormal hyperexcitation of neurons. Recent studies have suggested that the imbalance of excitation and inhibition (E/I) in the central nervous system is closely implicated in the etiology of epilepsy. In the brain, GABA is a major inhibitory neurotransmitter and plays a pivotal role in maintaining E/I balance. As such, altered GABAergic inhibition can lead to severe E/I imbalance, consequently resulting in excessive and hypersynchronous neuronal activity as in epilepsy. Phospholipase C (PLC) is a key enzyme in the intracellular signaling pathway and regulates various neuronal functions including neuronal development, synaptic transmission, and plasticity in the brain. Accumulating evidence suggests that neuronal PLC is critically involved in multiple aspects of GABAergic functions. Therefore, a better understanding of mechanisms by which neuronal PLC regulates GABAergic inhibition is necessary for revealing an unrecognized linkage between PLC and epilepsy and developing more effective treatments for epilepsy. Here we review the function of PLC in GABAergic inhibition in the brain and discuss a pathophysiological relationship between PLC and epilepsy.

Phospholipase C-ß1 potentiates glucose-stimulated insulin secretion.

PLC-ß exerts biologic influences through GPCR. GPCRs are involved in regulating glucose-stimulated insulin secretion (GSIS). Previous studies have suggested that PLC-ßs might play an important role in pancreatic ß cells. However, because of a lack of the specific inhibitors of PLC-ß isozymes and appropriate genetic models, the in vivo function of specific PLC-ß isozymes in pancreatic ß cells and their physiologic relevance in the regulation of insulin secretion have not been studied so far. The present study showed that PLC-ß1 was crucial for ß-cell function by generation of each PLC-ß conditional knockout mouse. Mice lacking PLC-ß1 in ß cells exhibited a marked defect in GSIS, leading to glucose intolerance. In ex vivo studies, the secreted insulin level and Ca2+ response in Plcb1f/f; pancreas/duodenum homeobox protein 1 (Pdx1)-Cre recombinase-estrogen receptor T2 (CreERt2) islets was lower than those in the Plcb1f/f islets under the high-glucose condition. PLC-ß1 led to potentiate insulin secretion via stimulation of particular Gq-protein-coupled receptors. Plcb1f/f; Pdx1-CreERt2 mice fed a high-fat diet developed more severe glucose intolerance because of a defect in insulin secretion. The present study identified PLC-ß1 as an important molecule that regulates ß cell insulin secretion and can be considered a candidate for therapeutic intervention in diabetes mellitus.-Hwang, H.-J., Yang, Y. R., Kim, H. Y., Choi, Y., Park, K.-S., Lee, H., Ma, J. S., Yamamoto, M., Kim, J., Chae, Y. C., Choi, J. H., Cocco, L., Berggren, P.-O., Jang, H.-J., Suh, P.-G. Phospholipase Cß1 potentiates glucose-stimulated insulin secretion.

Discovery of Chemicals to Either Clear or Indicate Amyloid Aggregates by Targeting Memory-Impairing Anti-Parallel Aß Dimers.

Amyloid-ß (Aß) oligomers are implicated in Alzheimer disease (AD). However, their unstable nature and heterogeneous state disrupts elucidation of their explicit role in AD progression, impeding the development of tools targeting soluble Aß oligomers. Herein parallel and anti-parallel variants of Aß(1-40) dimers were designed and synthesized, and their pathogenic properties in AD models characterized. Anti-parallel dimers induced cognitive impairments with increased amyloidogenesis and cytotoxicity, and this dimer was then used in a screening platform. Through screening, two FDA-approved drugs, Oxytetracycline and Sunitinib, were identified to dissociate Aß oligomers and plaques to monomers in 5XFAD transgenic mice. In addition, fluorescent Astrophloxine was shown to detect aggregated Aß in brain tissue and cerebrospinal fluid samples of AD mice. This screening platform provides a stable and homogeneous environment for observing Aß interactions with dimer-specific molecules.

Taurine Directly Binds to Oligomeric Amyloid-ß and Recovers Cognitive Deficits in Alzheimer Model Mice.

Alzheimer's disease (AD) is the most common cause of dementia leading to severe cognitive decline. During the progression of AD, amyloid-ß (Aß) monomers aggregate into neurotoxic soluble oligomeric Aß that causes cognitive impairments. Our previous study indicates that oral supplementation of taurine at 1000 mg/kg/day significantly ameliorates hippocampal-dependent cognitive deficits in APP/PS1 transgenic AD mouse model. However, Aß plaques and oligomeric Aß levels are not affected after administration of taurine and the oral dosage of taurine was relatively high. Thus, in this study, we focused on direct correlation between taurine and oligomeric Aß, causing memory deficits in a lower oral dosage of taurine, 250 mg/kg/day. We induced AD-like cognitive impairments to adult normal mice and orally administered taurine via drinking water for 10 days. We confirmed that taurine administration improved cognitive deficits in oligomeric Aß-infusion mice in Y-maze and passive avoidance tests without activity alteration of mice. In addition, we found that taurine directly bound to oligomeric Aß in surface plasmon resonance analyses. Our results propose that taurine can ameliorate cognitive impairment by directly binding to oligomeric Aß in oral administration of 250 mg/kg/day for 10 days.

Taurine-Carbohydrate Derivative Stimulates Fibrillogenesis of Amyloid-ß and Reduce Alzheimer-Like Behaviors.

Amyloid-ß (Aß) aggregates are a hallmark of Alzheimer's disease (AD). Through the misfolding process of Aß in the brain, oligomeric forms of Aß accumulate and significantly damage the brain cells inducing neuronal loss and cognitive dysfunctions that lead to AD. We hypothesized that decrease in Aß oligomers during the aggregation process might be able to reduce Aß-dependent brain damage. As taurine-like chemicals are often reported to have direct binding abilities to Aß, we prepared a chemical library that consisted of taurine-carbohydrate derivatives to search for molecules that target Aß and accelerate its fibrillogenesis. Here, we report that 1-deoxy-1-(2-sulfoethylamino)-D-fructose stimulates the formation of relatively less toxic Aß fibrils leading to prevention of cognitive deficits in AD acute model mice.

Bis Expression in Patients with Surgically Resected Lung Cancer and its Clinical Significance.

BACKGROUND: Bis, also known as BAG3, has been identified as a Bcl-2-interacting protein that enhances cellular anti-apoptotic activity. It is involved in cellular differentiation, angiogenesis, migration, and invasion in various tumors. The purpose of this study was to investigate the Bis expression pattern, and the clinical significance thereof, in patients with resected lung cancer. METHODS: We studied 121 lung cancer patients who underwent curative surgical resection. Patient clinicopathological characteristics were reviewed retrospectively from medical records, including tumor recurrence and survival. The expression of Bis protein in lung cancer tissues was evaluated by immunohistochemical staining and was assessed using a four-tiered intensity score system (negative, weak, moderate, strong). Enhanced Bis expression at the periphery of a tumor facing the adjacent nontumor region was referred as "marginal activity." RESULTS: Although Bis expression was higher in squamous cell carcinoma than in adenocarcinoma, marginal activity was higher in adenocarcinoma than in squamous cell carcinoma. All of the small cell carcinomas and lung cancer with neuroendocrine differentiation examined were negative for Bis expression. Compared with stage I lung cancer, patients with stage II and IIIA lung cancer exhibited higher Bis protein levels in lung tissues. Recurrence and survival rates did not differ significantly according to Bis expression intensity score or marginal activity. CONCLUSIONS: Our study demonstrated that Bis expression differed according to the histological type and pathological stage of the lung cancer. Further studies are needed to assess its use as a biomarker and its role in the molecular pathogenesis of lung cancer.

Glial GABA, synthesized by monoamine oxidase B, mediates tonic inhibition.

GABA is the major inhibitory transmitter in the brain and is released not only from a subset of neurons but also from glia. Although neuronal GABA is well known to be synthesized by glutamic acid decarboxylase (GAD), the source of glial GABA is unknown. After estimating the concentration of GABA in Bergmann glia to be around 5-10 mM by immunogold electron microscopy, we demonstrate that GABA production in glia requires MAOB, a key enzyme in the putrescine degradation pathway. In cultured cerebellar glia, both Ca(2+)-induced and tonic GABA release are significantly reduced by both gene silencing of MAOB and the MAOB inhibitor selegiline. In the cerebellum and striatum of adult mice, general gene silencing, knock out of MAOB or selegiline treatment resulted in elimination of tonic GABA currents recorded from granule neurons and medium spiny neurons. Glial-specific rescue of MAOB resulted in complete rescue of tonic GABA currents. Our results identify MAOB as a key synthesizing enzyme of glial GABA, which is released via bestrophin 1 (Best1) channel to mediate tonic inhibition in the brain.

Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKß inhibitors.

Inactivation of the NF-κB signaling pathway by inhibition of IKKß is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKß inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-α, which are well-known inflammatory responses generated by activated NF-κB. However, no inhibitory activity against IKKß was observed with these compounds. The thienopyrimidine-based analogues were subsequently screened for a target kinase, and FLT3, which is a potential target for acute myeloid leukemia (AML), was identified. Thienopyrimidine-based FLT3 inhibitors showed good inhibition profiles against FLT3 under 1µM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.

Comparison of the pharmacokinetic characteristics and bioequivalence between two nanosuspension formulations of megestrol acetate in healthy Korean male subjects.

Megestrol is commonly used to address appetite loss, cachexia, and significant weight loss in cancer or acquired immune deficiency syndrome patients. This study aimed to assess the pharmacokinetics and determine the bioequivalence of two orally administered megestrol acetate suspensions (625 mg/5 mL) in healthy Korean male subjects. A randomized, open-label, single-dose crossover study was conducted involving fifty-four healthy male subjects who were randomized into two sequence groups. Each subject received either a test or reference drug formulation of 625 mg/5 mL megestrol acetate with a two-week washout period between treatments. Plasma samples were collected before and up to 120 hours after administration, and their plasma drug concentrations were analyzed using validated liquid chromatography-mass spectrometry/mass spectrometry. The pharmacokinetic parameters were calculated, and bioequivalence was confirmed if the 90% confidence intervals of the geometric mean ratios were within the specified bounds of 80.00% to 125.00%. In total, fifty-two subjects completed the study, contributing to the pharmacokinetic analysis. The 90% confidence intervals for the geometric mean ratios of the test formulation compared to the reference formulation were 93.85% to 108.90% for maximum plasma concentration and 91.60% to 101.78% for area under the concentration-time curve from the point of administration to last time point of blood sampling. Throughout the study, no serious or unexpected adverse events were observed. The pharmacokinetic profiles of both formulations of megestrol acetate (625 mg) were comparable and well tolerated in healthy Korean male adult subjects. The test formulation met regulatory criteria for bioequivalence. Trial Registration: ClinicalTrials.gov Identifier: NCT06147908.

Early onset diagnosis in Alzheimer's disease patients via amyloid-ß oligomers-sensing probe in cerebrospinal fluid.

Amyloid-ß (Aß) oligomers are implicated in the onset of Alzheimer's disease (AD). Herein, quinoline-derived half-curcumin-dioxaborine (Q-OB) fluorescent probe was designed for detecting Aß oligomers by finely tailoring the hydrophobicity of the biannulate donor motifs in donor-π-acceptor structure. Q-OB shows a great sensing potency in dynamically monitoring oligomerization of Aß during amyloid fibrillogenesis in vitro. In addition, we applied this strategy to fluorometrically analyze Aß self-assembly kinetics in the cerebrospinal fluids (CSF) of AD patients. The fluorescence intensity of Q-OB in AD patients' CSF revealed a marked change of log (I/I0) value of 0.34 ± 0.13 (cognitive normal), 0.15 ± 0.12 (mild cognitive impairment), and 0.14 ± 0.10 (AD dementia), guiding to distinguish a state of AD continuum for early diagnosis of AD. These studies demonstrate the potential of our approach can expand the currently available preclinical diagnostic platform for the early stages of AD, aiding in the disruption of pathological progression and the development of appropriate treatment strategies.

2-Phenylbenzofuran derivatives alleviate mitochondrial damage via the inhibition of ß-amyloid aggregation.

To obtain modulators for reducing mitochondrial damage by the inhibition of Aß oligomer formation, 2-phenylbenzofuran derivatives were designed and prepared. Their inhibitory activity against Aß fibril formation was screened using ThT fluorescence assay, and the effect of derivatives on mitochondrial function was evaluated using JC-1 and MTT assay. 2-Phenylbenzofuran derivatives with dimethylamino group at p-position had an excellent inhibitory activity against Aß fibril formation. Particularly, compound 19m alleviated mitochondrial damage remarkably and possessed protective effects against Aß-induced cytotoxicity.

Therapeutic and pharmacokinetic characterizations of an anti-amyloidogenic bis-styrylbenzene derivative for Alzheimer's disease treatment.

Alzheimer's disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-ß. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F=46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD50 >2000 mg/kg) and hERG channel inhibition (14% at 10 µM) results indicated safety of KMS80013.

Carprofen alleviates Alzheimer-like phenotypes of 5XFAD transgenic mice by targeting the pathological hallmarks induced by amyloid-ß aggregation.

Alzheimer's disease (AD) is characterized by misfolding, oligomerization, and accumulation of amyloid-ß (Aß) peptides in the brain. Aß monomers transform into Aß oligomers, which are toxic species, inducing tau hyperphosphorylation and the downstream effects on microglia and astrocytes, triggering synaptic and cognitive dysfunctions. The oligomers then deposit into Aß plaques, primarily composed of ß-stranded fibrils, required for definitive AD diagnosis. As amyloid burden plays the pivotal role in AD pathogenesis, many efforts are devoted in preventing amyloidosis as a therapeutic approach to impede the disease progression. Here, we discovered carprofen, a non-steroidal anti-inflammatory drug, accelerates Aß aggregating into fibrils and increases Aß plaques when intraperitoneally injected to 5XFAD transgenic mouse model. However, the drug seems to alleviate the key Alzheimer-like phenotypes induced by Aß aggregation as we found attenuated neuroinflammation, improved post-synaptic density expression, associated with synaptic plasticity, and decreased phosphorylated tau levels. Carprofen also rescued impaired working memory as we discovered improved spontaneous alternation performance through Y-maze test assessed with Aß(1-42)-infused mouse model. Collectively, while carprofen accelerates the conversion of Aß monomers into fibrils in vitro, the drug ameliorates the major pathological hallmarks of AD in vivo.

Solid-phase synthesis and pathological evaluation of pyroglutamate amyloid-ß3-42 peptide.

Pyroglutamate amyloid-ß3-42 (AßpE3-42) is an N-terminally truncated and pyroglutamate-modified Aß peptide retaining highly hydrophobic, amyloidogenic, and neurotoxic properties. In Alzheimer's disease (AD) patients, AßpE3-42 peptides accumulate into oligomers and induce cellular toxicity and synaptic dysfunction. AßpE3-42 aggregates further seed the formation of amyloid plaques, which are the pathological hallmarks of AD. Given that AßpE3-42 peptides play critical roles in the development of neurodegeneration, a reliable and reproducible synthetic access to these peptides may support pathological and medicinal studies of AD. Here, we synthesized AßpE3-42 peptides through the microwave-assisted solid-phase peptide synthesis (SPPS). Utilizing thioflavin T fluorescence assay and dot blotting analysis with anti-amyloid oligomer antibody, the amyloidogenic activity of synthesized AßpE3-42 peptides was confirmed. We further observed the cytotoxicity of AßpE3-42 aggregates in cell viability test. To examine the cognitive deficits induced by synthetic AßpE3-42 peptides, AßpE3-42 oligomers were intracerebroventricularly injected into imprinting control region mice and Y-maze and Morris water maze tests were performed. We found that AßpE3-42 aggregates altered the expression level of postsynaptic density protein 95 in cortical lysates. Collectively, we produced AßpE3-42 peptides in the microwave-assisted SPPS and evaluated the amyloidogenic and pathological function of the synthesized peptides.