**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Olga Gursky

**Main Body of the Abstract**
Apolipoproteins are “amyloid signature proteins”, yet apolipoprotein-amyloid interactions are enigmatic. To understand how apoE interacts with Alzheimer’s amyloid-beta peptide in fibrillary deposits, the NMR structure of full-length human apoE was docked to four structures of patient-derived Abeta(1-40) and Abeta(1-42) fibrils determined previously using cryo-electron microscopy or solid-state NMR. Similar docking was done using the structures of human apoC-III and of an apolipoprotein consensus peptide. In all complexes, conformational changes were required to expose large hydrophobic faces of apolipoprotein amphipathic alpha-helices for sub-stoichiometric binding to hydrophobic surfaces on fibril sides or ends. Basic residues flanking the hydrophobic helical faces in apolipoproteins interacted favorably with acidic residue ladders in some amyloid polymorphs. Molecular dynamics simulations of selected apoE-fibril complexes confirmed their stability. Amyloid binding via cryptic sites, which became exposed upon opening of flexibly linked apolipoprotein alpha-helices, resembled apolipoprotein-lipid binding. This mechanism extends to other apolipoprotein-amyloid interactions. Apolipoprotein binding alongside fibrils could interfere with fibril fragmentation and secondary nucleation, while binding at the fibril ends could halt amyloid elongation and dissolution in a polymorph-specific manner. The proposed mechanism is supported by extensive prior experimental evidence and helps reconcile disparate reports on apoE’s role in Abeta aggregation. Furthermore, apoE domain opening and direct interaction of Arg/Cys158 with amyloid potentially contributes to isoform-specific effects in Alzheimer’s disease. In summary, current modeling supported by prior experimental studies suggests similar mechanisms for apolipoprotein-amyloid and apolipoprotein-lipid interactions; explains why apolipoproteins co-deposit with amyloids; and helps reconcile conflicting reports on the chaperone-like apoE action in Abeta aggregation.



**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Olga Gursky

**Main Body of the Abstract**
Apolipoproteins are “amyloid signature proteins”, yet apolipoprotein-amyloid interactions are enigmatic. To understand how apoE interacts with Alzheimer’s amyloid-beta peptide in fibrillary deposits, the NMR structure of full-length human apoE was docked to four structures of patient-derived Abeta(1-40) and Abeta(1-42) fibrils determined previously using cryo-electron microscopy or solid-state NMR. Similar docking was done using the structures of human apoC-III and of an apolipoprotein consensus peptide. In all complexes, conformational changes were required to expose large hydrophobic faces of apolipoprotein amphipathic alpha-helices for sub-stoichiometric binding to hydrophobic surfaces on fibril sides or ends. Basic residues flanking the hydrophobic helical faces in apolipoproteins interacted favorably with acidic residue ladders in some amyloid polymorphs. Molecular dynamics simulations of selected apoE-fibril complexes confirmed their stability. Amyloid binding _via_ cryptic sites, which became exposed upon opening of flexibly linked apolipoprotein alpha-helices, resembled apolipoprotein-lipid binding. This mechanism extends to other apolipoprotein-amyloid interactions. Apolipoprotein binding alongside fibrils could interfere with fibril fragmentation and secondary nucleation, while binding at the fibril ends could halt amyloid elongation and dissolution in a polymorph-specific manner. The proposed mechanism is supported by extensive prior experimental evidence and helps reconcile disparate reports on apoE’s role in Abeta aggregation. Furthermore, apoE domain opening and direct interaction of Arg/Cys158 with amyloid potentially contributes to isoform-specific effects in Alzheimer’s disease. In summary, current modeling supported by prior experimental studies suggests similar mechanisms for apolipoprotein-amyloid and apolipoprotein-lipid interactions; explains why apolipoproteins co-deposit with amyloids; and helps reconcile conflicting reports on the chaperone-like apoE action in Abeta aggregation.



Molecular modeling of apoE interactions with amyloid-beta fibrils from human brain suggests a structural basis for apolipoprotein co-deposition with amyloids PC1 (#28)

We invite you to attend the XIX International Symposium on Amyloidosis to be held in Rochester, MN.

This symposium is organized as a hybrid meeting (with the focus on in-person) held from Sunday, May 26 through Thursday, May 30, 2024.

Together with the ISA Board and members of Mayo Clinic, a very attractive scientific hybrid program is being planned. The program will cover a variety of types of systemic amyloidosis: ATTR (hereditary and wild-type), AL (light-chain), AA and less frequent forms. There will be key lectures, specific symposia including those company sponsored, oral presentations and poster sessions of accepted abstracts.

COURSE DESCRIPTION
This program will provide a comprehensive review of state-of-the-art education in systemic amyloidosis: basic science, pathophysiology, diagnosis, current and emerging treatments. Scientific presentations will include competitive oral and poster abstracts. The rapid evolution of scientific discovery and expanding treatment options has created tremendous interest in the field and this meeting will fill and important gap in educating scientists and clinicians.