2e2ded1ca08106db5debaef6c7049c6c ijms_24_08408.pdf bdf6af4a9dc9492eb18285ed923fd64dfc246b7c ijms_24_08408.pdf 402830784dcf919dcc9da5efb794233ae72bafe16414ef102223f1edef25b2ec ijms_24_08408.pdf Title: A40 Aggregation under Changeable Conditions Subject: Homeostasis is crucial for cell function, and disturbances in homeostasis can lead to health disorders. Under normal conditions, intracellular pH is maintained between 7.35 and 7.45. Altered endosomal and lysosomal pH together with a general drop in brain pH are associated with the aggregation of amyloid–peptide (A) and the development of Alzheimer’s disease. Under acidic conditions, close to the A isoelectric point, the absence of charges favors the formation of intermolecular contacts and promotes aggregation. Here, we analyzed how pH levels affect the aggregation of A40 considering the variations in brain pH and the coexistence of different aggregated conformations. Our results suggest that different macromolecular conformations can interact with each other and influence the aggregation process. In addition, we showed that neutral pH and physiological salt concentrations favor a slow aggregation, resulting in ordered, stable fibrils, with low cytotoxic effects. Overall, we highlight the complexity of the aggregation processes occurring in different physiological and pathological environments. Keywords: amyloid–peptide; charge repulsion; aggregation Author: Jofre Seira Curto, Maria Rosario Fernandez, Josep Cladera, Núria Benseny-Cases and Natalia Sanchez de Groot Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sun May 7 12:31:24 2023 CEST ModDate: Sun May 7 12:35:09 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4864323 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ZYYJXI+EURB10 Type 1 Builtin yes yes no 10 0 ENLEMO+VnURWPalladioL-Bold Type 1 Custom yes yes no 14 0 HBRMHV+VnURWPalladioL Type 1 Custom yes yes no 19 0 LEVXPH+EURM10 Type 1 Builtin yes yes no 23 0 PVVIKB+URWPalladioL-Bold Type 1 Custom yes yes no 27 0 VOWCAD+URWPalladioL-Roma Type 1 Custom yes yes no 32 0 ZGNTER+URWPalladioL-Ital Type 1 Custom yes yes no 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valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 545 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: pH and Salt Effect on A40 Aggregation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: pH Exchange and Cross-Seeding Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: ぁ㎒〴〰〠ぁででひづでちぴづび〠ごはへどっどぴべ〠 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Children: Item: Title: pH Effect on A40 Aggregation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Effect of pH Exchange and Cross-Seeding on A40 Aggregation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: A40 Aggregation under Complex Conditions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Material and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Children: Item: Title: ぁ㎒〴〰〠ぐづばぴどつづ〠ぐひづばちひちぴどはの〠 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: ThT Aggregation Kinetics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Dynamic Light Scattering Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Transmission Electron Microscopy Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Infrared Spectroscopy Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Cell Cytotoxicity Assay Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Info: Title: A40 Aggregation under Changeable Conditions Author: Jofre Seira Curto, Maria Rosario Fernandez, Josep Cladera, Núria Benseny-Cases and Natalia Sanchez de Groot Subject: Homeostasis is crucial for cell function, and disturbances in homeostasis can lead to health disorders. Under normal conditions, intracellular pH is maintained between 7.35 and 7.45. Altered endosomal and lysosomal pH together with a general drop in brain pH are associated with the aggregation of amyloid peptide (A) and the development of Alzheimer’s disease. Under acidic conditions, close to the A isoelectric point, the absence of charges favors the formation of intermolecular contacts and promotes aggregation. Here, we analyzed how pH levels affect the aggregation of A40 considering the variations in brain pH and the coexistence of different aggregated conformations. Our results suggest that different macromolecular conformations can interact with each other and influence the aggregation process. In addition, we showed that neutral pH and physiological salt concentrations favor a slow aggregation, resulting in ordered, stable fibrils, with low cytotoxic effects. Overall, we highlight the complexity of the aggregation processes occurring in different physiological and pathological environments. 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