**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.**
*Nikolaos Louros, VIB-KU Leuven Center for Brain and Disease Research
*Current address: Center for Alzheimer's and Neurodegenerative Diseases, UT Southwestern Medical Center, Dallas, Texas, USA

**Main Body of the Abstract**
Tauopathies constitute a group of neurodegenerative disorders characterized by a variety of tau amyloid fibril structures. Structural polymorphism across tauopathies implies that different pathological conditions influence the specific polymorphic form adopted in each disease. Nevertheless, the extent to which inherent structural tendencies of tau amyloid cores contribute to fibril polymorphism remains uncertain. Through a combination of experimental approaches, we here characterized in full the aggregation propensity of tau, revealing five local amyloid motifs that stabilize its various amyloid conformations. Of these five core segments, we identified a novel amyloidogenic motif, termed PAM4 (Polymorphic Amyloid Motif of Repeat 4), as a significant contributor to tau polymorphism. Analysis of per-residue contributions to the stability of fibril cores in various pathological tau structures suggests that PAM4 plays a central role in maintaining structural integrity across amyloid polymorphs. Consistent with this, cryo-EM structural analysis of fibrils formed from a synthetic PAM4 peptide reveals that the sequence adopts alternative structures closely corresponding to distinct disease-associated tau strains. Additionally, in-cell experiments demonstrate that the deletion of PAM4 hampers the cellular seeding efficiency of tau aggregates extracted from patients with Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy, emphasizing the pivotal role of PAM4 in these tauopathies. Collectively, our findings underscore the significance of the intrinsic structural tendencies of amyloid core segments in determining tau structure in cells and propagating amyloid structures in disease.



Local amyloid motifs mediate tau polymorphism and cellular propagation OC20 (#378)

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.