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1. α-CGRP disrupts amylin fibrillization and regulates insulin secretion: implications on diabetes and migraine

   https://doi.org/10.1039/D1SC01167G  

   Gray, Amber L.; Antevska, Aleksandra; Link, Benjamin A.; Bogin, Bryan; Burke, Susan J.; Dupuy, Samuel D.; Collier, J. Jason; Levine, Zachary A.; Karlstad, Michael D.; Do, Thanh D. (April 2021, Chemical Science)

   Despite being relatively benign and not an indicative signature of toxicity, fibril formation and fibrillar structures continue to be key factors in assessing the structure–function relationship in protein aggregation diseases. The inability to capture molecular cross-talk among key players at the tissue level before fibril formation greatly accounts for the missing link toward the development of an efficacious therapeutic intervention for Type II diabetes mellitus (T2DM). We show that human α-calcitonin gene-related peptide (α-CGRP) remodeled amylin fibrillization. Furthermore, while CGRP and/or amylin monomers reduce the secretion of both mouse Ins1 and Ins2 proteins, CGRP oligomers have a reverse effect on Ins1. Genetically reduced Ins2, the orthologous version of human insulin, has been shown to enhance insulin sensitivity and extend the life-span in old female mice. Beyond the mechanistic insights, our data suggest that CGRP regulates insulin secretion and lowers the risk of T2DM. Our result rationalizes how migraine might be protective against T2DM. We envision the new paradigm of CGRP : amylin interactions as a pivotal aspect for T2DM diagnostics and therapeutics. Maintaining a low level of amylin while increasing the level of CGRP could become a viable approach toward T2DM prevention and treatment. 

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2. Direct Observation of Amyloid-β 42 Oligomer, Fibril, and Amorphous Aggregate Growth and Dissolution at Biomimetic Concentrations

   https://doi.org/10.1021/acs.jpcb.5c03842  

   Sunil_Menon, Radhika; Wolynes, Peter G; Vekilov, Peter G (September 2025, The Journal of Physical Chemistry B)

   The aggregation pathways of A beta 42 peptides are complex and can lead to both amyloids and nonamyloid aggregates. We use in situ atomic force microscopy imaging to monitor the assembly of aggregate structures and their dynamics. Two aggregation pathways emerge, one leading to amyloid fibrils and a second one that includes the formation of oligomers and apparently amorphous aggregates, which we identify as nonamyloid. Whereas the fibrils seem to require elevated peptide concentration to nucleate and grow, oligomers and amorphous aggregates form at near-physiological peptide concentrations. On the time scales of the experiments, the two aggregation pathways do not cross: the oligomers and aggregates do not participate in the fibrillization pathway and, analogously, secondary nucleation assisted by mature fibrils does not produce misfolded aggregates. We show that distinct A beta 42 fibril polymorphs form and coexist under identical conditions. Mature fibrils serve as substrates for secondary nucleation that leads to forked, branched, and thicker fibrils and, importantly, produces new fibril fragments. A beta 42 fibrils accumulate structural defects, with more defects generated at higher peptide concentrations. The defects lead to substantial variations of growth rate both over time and between different fibrils. The average growth rates of A beta 42 fibrils are about 50-fold faster than those of A beta 40 fibrils. Our findings are consistent with the basic premise of the polymorph selection hypothesis, according to which the late onset of Alzheimer's disease, its high clinical variability, and the presence of amyloid plaques in healthy individuals have their origins in differing toxicities and aggregation kinetics of distinct A beta structural polymorphs. 

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3. Molecular insights into the surface-catalyzed secondary nucleation of amyloid-β ₄₀ (Aβ ₄₀ ) by the peptide fragment Aβ _16–22

   https://doi.org/10.1126/sciadv.aav8216  

   Bunce, Samuel J.; Wang, Yiming; Stewart, Katie L.; Ashcroft, Alison E.; Radford, Sheena E.; Hall, Carol K.; Wilson, Andrew J. (June 2019, Science Advances)

   Understanding the structural mechanism by which proteins and peptides aggregate is crucial, given the role of fibrillar aggregates in debilitating amyloid diseases and bioinspired materials. Yet, this is a major challenge as the assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of Aβ 40 and Aβ 16–22 , two widely studied peptide fragments of Aβ 42 implicated in Alzheimer’s disease. We demonstrate that Aβ 16–22 increases the aggregation rate of Aβ 40 through a surface-catalyzed secondary nucleation mechanism. Discontinuous molecular dynamics simulations allowed aggregation to be tracked from the initial random coil monomer to the catalysis of nucleation on the fibril surface. Together, the results provide insight into how dynamic interactions between Aβ 40 monomers/oligomers on the surface of preformed Aβ 16–22 fibrils nucleate Aβ 40 amyloid assembly. This new understanding may facilitate development of surfaces designed to enhance or suppress secondary nucleation and hence to control the rates and products of fibril assembly. 

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4. Water‐Mediated Phosphoryl Wires Stabilize Pathological Tau Fibrils

   https://doi.org/10.1002/anie.202521499  

   Potnuru, Lokeswara Rao; DuBose, Austin; Mon, Fiona; Nowotarski, Mesopotamia S; Vigers, Michael; Zhang, Boqin; Han, Chung‐Ta; Straub, John E; Han, Songi (May 2026, Angewandte Chemie International Edition)

   ABSTRACT Hyperphosphorylation of tau is a hallmark of tauopathies, with specific phosphorylation sites elevated in pathological fibrils. However, the molecular role of this post‐translational modification (PTM) in driving tau aggregation remains unclear. In‐register fibril assembly places phosphoryl groups on adjacent monomers at ∼4.8 Å spacing, requiring an energetically favorable arrangement. Conventional intuition holds that closely packed phosphoryl groups should be electrostatically unfavorable. We test the opposing hypothesis: that phosphoryl groups within the fibril core associate into an extended “wire” that stabilizes the amyloid fibril. We examined two phosphorylation sites linked to neurodegeneration, serine 305 (S305^p) and tyrosine 310 (Y310^p), using seeding‐competent fibrils of the tau peptide jR2R3‐P301L. Multiple‐quantum spin counting (MQ‐SC) by³¹P solid‐state NMR with dynamic nuclear polarization (DNP) revealed at least six phosphorus spins linearly arranged within a protofibril, consistent with a MQ coherence order of four. Molecular dynamics simulations identified water‐mediated phosphoryl wire geometries, and 2D¹H–³¹P heteronuclear correlation NMR confirmed water‐bridged phosphoryl‐phosphoryl contacts. Denaturation experiments showed that S305 phosphorylation increased fibril stability relative to the unmodified peptide. These findings show that phosphorylation within the tau fibril core promotes fibril registry and stability through water‐mediated, hydrogen‐bonded phosphoryl wires, which may be a structural signature for next‐generation pathological tau binders. 

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5. Mapping the configurational landscape and aggregation phase behavior of the tau protein fragment PHF6

   https://doi.org/10.1073/pnas.2309995120  

   Pretti, Evan; Shell, M. Scott (November 2023, Proceedings of the National Academy of Sciences)

   The PHF6 (Val-Gln-Ile-Val-Tyr-Lys) motif, found in all isoforms of the microtubule-associated protein tau, forms an integral part of ordered cores of amyloid fibrils formed in tauopathies and is thought to play a fundamental role in tau aggregation. Because PHF6 as an isolated hexapeptide assembles into ordered fibrils on its own, it is investigated as a minimal model for insight into the initial stages of aggregation of larger tau fragments. Even for this small peptide, however, the large length and time scales associated with fibrillization pose challenges for simulation studies of its dynamic assembly, equilibrium configurational landscape, and phase behavior. Here, we develop an accurate, bottom-up coarse-grained model of PHF6 for large-scale simulations of its aggregation, which we use to uncover molecular interactions and thermodynamic driving forces governing its assembly. The model, not trained on any explicit information about fibrillar structure, predicts coexistence of formed fibrils with monomers in solution, and we calculate a putative equilibrium phase diagram in concentration-temperature space. We also characterize the configurational and free energetic landscape of PHF6 oligomers. Importantly, we demonstrate with a model of heparin that this widely studied cofactor enhances the aggregation propensity of PHF6 by ordering monomers during nucleation and remaining associated with growing fibrils, consistent with experimentally characterized heparin–tau interactions. Overall, this effort provides detailed molecular insight into PHF6 aggregation thermodynamics and pathways and, furthermore, demonstrates the potential of modern multiscale modeling techniques to produce predictive models of amyloidogenic peptides simultaneously capturing sequence-specific effects and emergent aggregate structures. 

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