bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2026–10–25
thirteen papers selected by
Verena Kohler, Umeå University
  1. Imaging nanoscopic co-assemblies of α-synuclein and Tau in human samples.
  2. Liquid-liquid phase separation in neurodegenerative diseases: Mechanisms, pathological transitions, and therapeutic opportunities.
  3. Metal Ions and Protein Aggregation: Unraveling Molecular Interactions and Theranostic Prospects in Proteinopathies.
  4. The morphology of α-synuclein fibrils changes during formation, storage, and upon exposure to ligands.
  5. Cryo-EM advances in TDP-43 amyloid fibrils structure determination.
  6. Monitoring amyloid formation from natively folded proteins to amyloid fibrils by NMR spectroscopy.
  7. Receptor-Specific ER-Phagy in Neurodegenerative Diseases: Molecular Mechanisms and Emerging Therapeutic Opportunities.
  8. N-Glycosylation in the Receptor Binding Domain serves as aggregation gatekeeper of the SARS CoV2 Spike glycoprotein folding.
  9. Rationally Designed Peptides and Peptoids as Inhibitors of Amyloid-β (Aβ) Aggregation.
  10. Residue-Resolved Mapping of Heterogeneous Structural Organization during Native-to-Amyloid Transition of an Amyloidogenic Protein.
  11. Discovery of benzoxazole derivatives as novel α-synuclein aggregate ligands with potential for PET tracer development.
  12. How a Single-Chain Polystyrene Nanoparticle Dictates α-Synuclein Adsorption and Intramolecular β-Sheet Nucleation.
  13. Investigating Structural Heterogeneities of Amyloid Aggregates with Spatially Resolved Infrared Spectroscopy.
  1. Nat Commun. 2026 09 18. pii: 10951. [Epub ahead of print]17(1):
    Imaging nanoscopic co-assemblies of α-synuclein and Tau in human samples.
    Yu P Zhang, Amber Wallis, Clara Obensa Bertroli, Cherida Zhang, Melanie Burke, Florence Layburn, Evgeniia Lobanova, Martin Furlepa, Shekhar Kedia, Yuhao Cui, Prasanna Suresh, Woo Suk Yang, Annelies Quaegebeur, Tim Bartels, Caroline H Williams-Gray, David Klenerman.
      α-synuclein (αS), amyloid-β (Aβ), and Tau aggregates are hallmarks of many neurodegenerative diseases, yet the prevalence and nature of their nanoscopic co-assemblies remain poorly understood. Here, we adapt a single-molecule pull-down (SiMPull) assay to profile αS, Aβ, and Tau co-assemblies across post-mortem brain tissue homogenates, soluble brain fractions, human serum, cerebrospinal fluid, and saliva. We show that αS-Tau co-assemblies are abundant across all sample matrices, accounting for ~10-70% of total αS aggregates in both Parkinson's disease (PD) and control samples. Notably, αS-Tau co-assemblies in soluble brain fractions from controls exhibit higher Proteinase K (PK) resistance than those from PD cases. Biophysically, Tau accelerates αS aggregation in simple in vitro systems, but this effect is suppressed in complex environments. Together, this work establishes a framework for probing co-assemblies, revealing that αS-Tau species possess heterogeneous biophysical features and are unlikely to act as a single, uniformly toxic species in PD pathology.
    DOI:  https://doi.org/10.1038/s41467-026-77728-1
  2. Sci Prog. 2026 Oct-Dec;109(4):109(4): 368504261499190
    Liquid-liquid phase separation in neurodegenerative diseases: Mechanisms, pathological transitions, and therapeutic opportunities.
    Jinxi Huang, Shengxi Zhang, Dan Zhang, Tianhang Yang, Can Li, Mengjia He, Jialin Wang, Tao Song, Xianyao Wang, Yanxin Lu, Qinghong Kong, Jun Tan, Jidong Zhang.
      Liquid-liquid phase separation (LLPS) provides a biophysical framework for understanding biomolecular organization, yet its pathological relevance in neurodegeneration remains incompletely resolved. In this narrative review, we critically synthesize current evidence on LLPS in Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, focusing on mutant huntingtin, α-synuclein, amyloid-β, tau, TDP-43, and FUS. We first outline the molecular principles-including intrinsic disorder, multivalent interactions, and environmental sensitivity-that govern their phase behavior. We then examine how dynamic condensates may, under specific cellular contexts, transition toward less reversible oligomeric, gel-like, or solid assemblies, integrating evidence from in vitro, cellular, and in vivo studies. Importantly, current evidence does not support LLPS as a universal or obligatory precursor of pathological aggregation; rather, its biological consequences appear to depend on condensate composition, material properties, subcellular localization, and proteostasis capacity, while direct demonstration of disease-relevant condensates in vivo remains limited. We further discuss whether aberrant LLPS represents a cause, consequence, or context-dependent component of neurodegeneration and highlight emerging strategies that modulate condensate formation, maturation, or clearance while preserving physiological functions. Overall, this review defines both the mechanistic potential and current limitations of the LLPS framework and identifies key questions that must be addressed before pathological phase-state modulation can become a clinically actionable therapeutic strategy.
    Keywords:  Biomolecular condensates; Intrinsically disordered proteins; Liquid-liquid phase separation; Neurodegenerative diseases; Protein aggregation
    DOI:  https://doi.org/10.1177/00368504261499190
  3. Chem Rev. 2026 Sep 23. 126(18): 10249-10333
    Metal Ions and Protein Aggregation: Unraveling Molecular Interactions and Theranostic Prospects in Proteinopathies.
    Danilo Milardi, Jiyeon Han, Hyuck Jin Lee, Feng Ding, Yifat Miller, Peter Faller, Ashley I Bush, Peter J Crouch, David I Finkelstein, Kay L Double, Aleksandar Jeremic, Mi Hee Lim, Ayyalusamy Ramamoorthy.
      Protein aggregation is a pathological process associated with several human diseases termed proteinopathies, including neurodegenerative and metabolic disorders such as Alzheimer's disease, Parkinson's disease, type II diabetes, amyotrophic lateral sclerosis, and Huntington's disease. In these conditions, specific proteins misfold and accumulate into insoluble aggregates, disrupting normal cellular function and contributing to disease progression. Many studies have investigated the molecular mechanisms that underlie the aggregation pathways, the structure of aggregates, such as oligomeric intermediates and fibrils, and their cellular toxicity. Studies have also investigated the effects of cofactors like metals, lipids, other amyloid proteins, and small molecules. Recent research has increasingly emphasized the critical roles of metal ions such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) in amyloid aggregation and toxicity. Alterations in metal ion transport, binding, or redox activity have been linked to the onset and progression of several amyloid-associated diseases. These metal ions can interact directly with amyloidogenic proteins, influencing their structural conformation, aggregation kinetics, and propensity to form toxic oligomers. This review aims to advance our understanding of how the regulation of metal ions within cells and their dysfunction contribute to the accumulation of harmful proteins, which is a key factor in proteinopathies. By examining the interactions between metal ions and key amyloidogenic proteins─including amyloid-β (Aβ), α-synuclein, tau, superoxide dismutase 1 (SOD1), human islet amyloid polypeptide (hIAPP), and insulin─we highlight both common and unique pathways through which metal ions influence protein aggregation. Additionally, this review explores the impact of metal ions on protein clearance mechanisms, such as autophagy and the ubiquitin-proteasome system, as well as emerging theranostic strategies. These include metal chelation therapies, metal-based imaging agents, and multifunctional compounds designed to restore metal balance while preventing aggregation and toxicity. By integrating biochemical, cellular, and therapeutic insights, this review contributes to a deeper understanding of the metallobiology of proteinopathies and supports the development of novel diagnostic and treatment approaches targeting metal-protein interactions.
    DOI:  https://doi.org/10.1021/acs.chemrev.5c00420
  4. Org Biomol Chem. 2026 Oct 19.
    The morphology of α-synuclein fibrils changes during formation, storage, and upon exposure to ligands.
    Timothy S Chisholm.
      Protein fibrils are pathological hallmarks of many neurodegenerative diseases, including Parkinson's disease. The preparation of α-synuclein (αSyn) fibrils in vitro is widely used in research relating to these conditions. However, αSyn fibrils exhibit substantial structural polymorphism. How fibril morphology evolves during formation, storage, or in the presence of small molecule ligands is poorly understood. Here, the evolution of αSyn fibril morphology was investigated using fluorescence assays, circular dichroism, transmission electron microscopy, and ligand profiling. Fibril morphology was found to evolve continuously during both aggregation of αSyn and subsequent storage, even at -79 °C. The inclusion of ligands, such as Thioflavin X, during aggregation affected both the reaction kinetics and the fibril morphologies formed. The addition of ligands to pre-formed fibrils also produced changes in fibril morphology. As different fibril morphologies exhibit distinct properties, more careful characterization and controls are required to ensure reproducibility and reliable interpretation of results. Additionally, these findings suggest the potential to use ligands to remodel fibril structure, possibly allowing for pathological morphologies to be converted to less pathological forms.
    DOI:  https://doi.org/10.1039/d6ob00760k
  5. Neurobiol Dis. 2026 Oct 17. pii: S0969-9961(26)00405-5. [Epub ahead of print] 107659
    Cryo-EM advances in TDP-43 amyloid fibrils structure determination.
    Zhengdong Xu, Xi Chen, Wenjuan Yi.
      TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein whose pathological aggregation characterizes a spectrum of neurodegenerative disorders known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and chronic traumatic encephalopathy (CTE). Recent breakthroughs in cryo-electron microscopy (cryo-EM) have revolutionized our understanding of these diseases by resolving the atomic structures of TDP-43 amyloid fibrils. These structural insights have been pivotal in elucidating the transition from functional liquid-liquid phase separation (LLPS) to irreversible solid-state aggregation. This review synthesizes key cryo-EM findings from 2019 to 2026, encompassing fibrils formed by the full-length low-complexity domain, disease-relevant core fragments, and filaments extracted directly from patient tissues, as well as the pathological implications of distinct structural polymorphs. These findings not only deepen our understanding of the brain science aspects of the pathogenesis of TDP-43 proteinopathies, but also provide an important structural basis for the development of specific conformational diagnostic methods and targeted therapeutic drugs.
    Keywords:  Amyloid; Brain science; Cryo-EM; TDP-43; TDP-43 proteinopathies
    DOI:  https://doi.org/10.1016/j.nbd.2026.107659
  6. Biophys Chem. 2026 Oct 15. pii: S0301-4622(26)00156-0. [Epub ahead of print]340 107723
    Monitoring amyloid formation from natively folded proteins to amyloid fibrils by NMR spectroscopy.
    Jyoti Singh, Tejaswini Pradhan.
      Amyloids are insoluble protein aggregates that arise through protein misfolding and are associated with numerous neurodegenerative disorders, systemic amyloidosis, and other human diseases. Nuclear magnetic resonance (NMR) spectroscopy, encompassing both solution-state and solid-state approaches, offers unique capabilities to investigate each stage of the complex amyloid formation pathway, from soluble monomeric precursors through transient intermediate states and oligomeric assemblies to highly ordered mature fibrils. This residue-specific and atomic-level characterization of the aggregation process is difficult to achieve using other biophysical techniques. NMR is particularly well suited for elucidating the mechanisms of amyloid formation because it provides detailed structural and dynamic information across multiple aggregation states at molecular resolution. This review highlights the application of solution-state and solid-state NMR methods in characterizing the conversion of natively folded amyloidogenic proteins into amyloid fibrils, with particular emphasis on the identification and characterization of transient intermediates, including both observable and "invisible" species, high-molecular-weight oligomers, and insoluble fibrillar aggregates. Representative examples of natively folded amyloidogenic precursor proteins are discussed, together with an overview of the NMR method used to elucidate their misfolding and aggregation mechanisms. Collectively, these studies demonstrate the power of NMR spectroscopy in providing mechanistic and structural insights into amyloid formation at residue-level resolution.
    Keywords:  Aggregation; Amyloid fibrils; Intermediate states; NMR spectroscopy; Oligomers; Transient state
    DOI:  https://doi.org/10.1016/j.bpc.2026.107723
  7. Ageing Res Rev. 2026 Oct 22. pii: S1568-1637(26)00418-6. [Epub ahead of print] 103426
    Receptor-Specific ER-Phagy in Neurodegenerative Diseases: Molecular Mechanisms and Emerging Therapeutic Opportunities.
    Suramya Malhotra, Rajat Sandhir.
      Neurodegenerative diseases (NDs) constitute a major global health burden driven by rising life expectancy and the lack of disease-modifying therapies. Central to these progressive pathologies is the accumulation and aggregation of conformationally altered proteins, categorizing them as 'proteinopathies'. These aberrant aggregates disrupt cellular homeostasis and trigger chronic stress responses that drive progressive neuronal dysfunction and loss. The endoplasmic reticulum (ER) is a dynamic organelle defined by remarkable structural diversity and functional plasticity, that preserves cellular homeostasis by orchestrating protein folding and quality control, lipid biosynthesis, calcium sequestration and metabolic detoxification. However, sustained ER stress and functional dysregulation are increasingly implicated in neurodegenerative cascades. In this context, ER-selective autophagy (ER-phagy) has emerged as an indispensable quality-control pathway. Mediated by dedicated ER-phagy receptors that target distinct subdomains for lysosomal clearance, this pathway preserves organellar integrity and mitigates proteotoxic burden in post-mitotic neurons. Nonetheless, the full mechanistic landscape of ER-phagy remains poorly defined, with receptor-specific functions, regulatory signalling networks and CNS expression profiles only beginning to be resolved. This review synthesizes current insights into ER-phagy in neurodegeneration, dissects receptor-specific mechanisms, and highlights emerging pharmacological interventions. Ultimately, the therapeutic potential of modulating receptor-specific ER-phagy as an untapped strategy to resolve ER stress, re-establish neuronal proteostasis and to combat neurodegenerative conditions is highlighted.
    Keywords:  Autophagy; ER-phagy; Endoplasmic Reticulum; Misfolded protein; Neurodegenerative diseases; Proteinopathy
    DOI:  https://doi.org/10.1016/j.arr.2026.103426
  8. J Biol Chem. 2026 Oct 22. pii: S0021-9258(26)02553-6. [Epub ahead of print] 113681
    N-Glycosylation in the Receptor Binding Domain serves as aggregation gatekeeper of the SARS CoV2 Spike glycoprotein folding.
    Anita Kumari, Beena Krishnan.
      The SARS CoV2 Spike is a multi-domain surface glycoprotein that binds human ACE2 via its receptor binding domain (RBD-CoV2) initiating the viral infection. Several aggregation prone regions are predicted in the Spike-CoV2 sequence. Here, we describe the intrinsic aggregation feature and characterization of RBD-CoV2 aggregates of the Wuhan variant in the context of its folding. In agreement with its predicted aggregation-prone nature, recombinant RBD-CoV2 in E. coli exclusively forms inclusion bodies that binds Thioflavin S dye. In vitro refolding of pure denatured RBD-CoV2 results in extensive aggregation yielding very low amounts of soluble functional protein. The RBD-CoV2 in vitro aggregates contain β-sheet structure as revealed by the Raman spectral analysis, bind amyloid-specific AmyTracker 630 and ProteoStat dyes, and have clustered sphere-like morphology. Similarly, the non-glycosylated RBD-CoV2 missing the N-glycan on Asn331 and Asn343, an equivalent to EcRBD, is not secreted, but retained in the endoplasmic reticulum of HEK293T cells. The ProteoStat dye binding indicates intracellular accumulation of the N-glycan RBD variants as amyloids in live cells. Furthermore, selective removal of both RBD N-glycans results in severe secretion defect of the Spike ectodomain, and markedly reduced syncytia formation in cells expressing glycan variants of membrane-bound Spike. Our study thus conclusively demonstrates that the essential role of RBD N-glycans is to prevent misfolding and aggregation of RBD-CoV2 and Spike-CoV2. The presence of N-glycan at either one of the two Asn in RBD significantly reduces misfolding of the full length Spike-CoV2, and the absence of both glycans results in RBD-CoV2 to form amyloids.
    Keywords:  Electron microscopy; N-linked glycosylation; Protein aggregation; Protein folding; RBD; Raman spectroscopy; SARS CoV2; Spherical amyloid; Spike; Syncytia
    DOI:  https://doi.org/10.1016/j.jbc.2026.113681
  9. Bioconjug Chem. 2026 Sep 16. 37(9): 1739-1770
    Rationally Designed Peptides and Peptoids as Inhibitors of Amyloid-β (Aβ) Aggregation.
    Xiaoping Huang, Sijie Ma, Xiang Li, Jie Pan.
      Peptide and peptoid are two types of peptidomimetics can be used as drugs for diseases. One of the main hallmarks in Alzheimer's Disease (AD) is Aβ aggregation. Due to the natural affinity between peptide and Aβ proteins, peptide therapeutics are found out to be suitable for the disease, as they are almost nontoxic, possess good biocompatibility and are structurally changeable. This review mainly focuses on peptide and peptoid as inhibitors targeting Aβ protein, elaborating on their design strategies and some of their inhibitory effects, providing diverse potential compounds for the treatment of AD. The involved peptide inhibitors are classified into three major categories based on their structural features: inhibitors based on the natural Aβ sequence, inhibitors based on non-natural Aβ sequences, and inhibitors conjugated with small molecule compounds. To facilitate understanding of the development process of each type of inhibitor, we have expounded on each major category in terms of chronological order, specialty and importance. It also summarized the challenges and design strategies faced by peptide inhibitors in targeting Aβ aggregation. This review provides a valuable resource for researchers in the field of synthetic peptide and their biomedical applications, offering structural insights into the design of new peptide for better diagnosis and therapeutic applications.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.6c00145
  10. Biochemistry. 2026 Oct 06. 65(19): 3003-3016
    Residue-Resolved Mapping of Heterogeneous Structural Organization during Native-to-Amyloid Transition of an Amyloidogenic Protein.
    Sonal R More, Prajna Mishra, Santosh Kumar Jha.
      Protein misfolding and aggregation in neuronal cells are key molecular events underlying several fatal neurodegenerative disorders. Effective therapeutic intervention requires residue-resolved structural information on the early aggregation intermediates that precede amyloid formation. However, these transient and heterogeneous species remain poorly characterized because of their dynamic nature and the limitations of conventional structural approaches. Here, we employ a multisite fluorescence approach to obtain residue-specific insights into the misfolding and aggregation pathway of the nucleic acid-binding domain of TDP-43. Using a library of single-tryptophan-single-cysteine mutants combined with site-selective labeling, we systematically probe intramolecular distances, local solvation, conformational rigidity, and structural fluctuations across native, molten globule, oligomeric, and amyloid states. The results reveal that the early amyloidogenic molten globule retains native-like secondary structure but undergoes heterogeneous structural reorganization, including simultaneous local expansion and compaction, as revealed by multisite Förster resonance energy transfer. Residue-specific analyses also identify early unfolding sites and regions that progressively become incorporated into the amyloid core. These findings provide a residue-resolved view of the structural transitions that link native conformations to aggregation-prone states and establish a framework for understanding early events in TDP-43 misfolding.
    DOI:  https://doi.org/10.1021/acs.biochem.6c00438
  11. Eur J Med Chem. 2026 Oct 20. pii: S0223-5234(26)00893-7. [Epub ahead of print]321(Pt 2): 119448
    Discovery of benzoxazole derivatives as novel α-synuclein aggregate ligands with potential for PET tracer development.
    Yuanlong Wang, Jiale Qin, YiKun Zhang, YongKang Wang, Bin Ji, Yong Chu.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, and the abnormal aggregation of α-synuclein (α-Syn) constitutes its core pathological hallmark. Positron emission tomography (PET) imaging of cerebral α-Syn aggregates holds great promise for the early diagnosis of PD. However, the imaging quality critically depends on the ligands with high binding affinity and selectivity for α-Syn aggregates. In this work, we developed a new type of benzoxazole-based α-Syn aggregate ligands via an SPR-based screening. Among them, candidates D15 (KD = 0.12 μM) and D16 (KD = 0.08 μM) exhibited high binding affinities for α-Syn aggregates in vitro and good potency in the SH-SY5Y cellular model and brain tissues from α-Syn PFF-injected PD mouse models, as well as excellent selectivity for tau and Aβ aggregates in rTg4510 and APP23 transgenic mouse brain sections. Thanks to their favorable blood-brain barrier permeability and suitable structures for radiolabeling for PET imaging, these new ligands represent promising candidates for the development of α-Syn PET radiotracers, offering a valuable foundation for the early diagnosis of PD and related synucleinopathies.
    Keywords:  Benzoxazole derivatives; PET tracer; Parkinson's disease; Structure-activity relationship; α-synuclein ligands
    DOI:  https://doi.org/10.1016/j.ejmech.2026.119448
  12. Langmuir. 2026 Sep 22. 42(37): 27464-27470
    How a Single-Chain Polystyrene Nanoparticle Dictates α-Synuclein Adsorption and Intramolecular β-Sheet Nucleation.
    Kang Wang, Shuai Gong, Yifeng Sheng, Lei Shen.
      A growing number of studies have detected nanoplastics, particularly polystyrene (PS) nanoparticles, in human blood and various critical tissues. Nevertheless, the molecular mechanisms by which their physical size modulates the aggregation of disease-related proteins remain poorly understood. Here, using well-tempered metadynamics simulations, we demonstrate that single-chain PS nanoparticles with a degree of polymerization N collapse into spherical globules in water, following a scaling law of radius of gyration Rg ∼ N1/3, and that their size critically determines the conformational fate of alpha-synuclein (αS), a key protein in Parkinson's disease. Within our single-chain simulation framework, we observe a sensitive size-dependent transition regime around N = 75 to 80 (Rg = 1.14 to 1.16 nm), where PS nanoparticles transition from insufficient surface area to a threshold capable of encapsulating the αS chain. The partially exposed protein chain subsequently folds into stable intramolecular β-sheet domains, representing the initial nucleation step toward amyloid aggregation. Conversely, nanoparticles with N ≥ 80 (Rg ≥ 1.16 nm) present a sufficiently large hydrophobic surface to completely encapsulate αS through dominant hydrophobic and π-π interactions, effectively suppressing the intramolecular β-sheet nucleation. These findings reveal that smaller nanoplastics may inadvertently promote protein misfolding, which may implicitly lower the likelihood of downstream intermolecular aggregation. Our work establishes a quantitative, size-dependent hazard principle for nanoplastic neurotoxicity and provides a molecular foundation for assessing the risk of environmentally derived nanoparticles in synucleinopathies.
    DOI:  https://doi.org/10.1021/acs.langmuir.6c03846
  13. Acc Chem Res. 2026 Oct 20. 59(20): 3294-3307
    Investigating Structural Heterogeneities of Amyloid Aggregates with Spatially Resolved Infrared Spectroscopy.
    Divya Baghel, Ayanjeet Ghosh.
      The aggregation of proteins into fibrillar amyloids is central to the pathology of neurodegenerative disorders. However, the relationship between the structure of amyloid aggregates and disease progression remains incompletely understood, in part because amyloid systems are intrinsically heterogeneous: structurally distinct species coexist at every stage of aggregation, and conventional ensemble-averaged methods cannot always resolve them. This Account describes how infrared spectroscopy can be coupled to different imaging modalities to resolve this heterogeneity at multiple length scales: from single-aggregate level to amyloid species in diseased brain tissues. Our findings demonstrate that (i) early stage tau fibrils exhibit pronounced structural polymorphism without morphological differences, converging to a single dominant conformation upon maturation that unexpectedly includes antiparallel β-sheet structure; (ii) Aβ42 oligomeric heterogeneity propagates through protofibrils into fibrils, where structurally distinct domains coexist along a single fibril, demonstrating that amyloid fibrils can deviate significantly from the canonical parallel cross-β architecture; (iii) Aβ(16-22) fibrils undergo a parallel-to-antiparallel β-sheet transition during maturation through disordered intermediates without morphological change, providing direct evidence of spontaneous structural reorganization in fibrillar species. Beyond single-protein systems, (iv) Aβ42 forms structurally distinct mixed polymorphs when aggregated with sequentially or structurally heterotypic seeds and when coaggregated with α-synuclein, establishing heterotypic interactions as an underappreciated source of aberrant aggregate structures; (v) coaggregation of Aβ with the islet amyloid polypeptide (IAPP) from the monomeric state produces a unique heterotypic polymorph in which both peptides adopt non-native structures, whereas cross-seeding with preformed IAPP fibrils yields predominantly homotypic Aβ aggregates, demonstrating that conformational flexibility at the monomeric stage is required for heterotypic fibril formation. These molecular-level findings are complemented by tissue-scale evidence: (vi) discrete frequency IR imaging reveals that amyloid plaques in AD brain exhibit chemical and structural heterogeneities not reflected in morphology, consistent with in vitro observations; and (vii) optical photothermal infrared (O-PTIR) spectroscopic imaging of vascular amyloid deposits in cerebral amyloid angiopathy (CAA) reveals a disease-stage-dependent increase in antiparallel β-sheet content that correlates specifically with colocalized lipids, recapitulated in vitro by coaggregating Aβ40 with lipid extracts. Collectively, these findings support the view that structural heterogeneity is not merely an artifact of in vitro conditions but a property that can persist in human brain tissues and illustrate how spatially resolved IR spectroscopy can complement cryogenic electron microscopy (cryo-EM) and solid-state NMR in the study of amyloid pathology.
    DOI:  https://doi.org/10.1021/acs.accounts.6c00390
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