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The Relationship between Ergothioneine, Allantoin and Neocortical Amyloid Load.

Alzheimer's disease (AD) is characterised by hallmark pathology of amyloid beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles in the brain. Ergothioneine (ET) is a potent antioxidant, and anti-inflammatory compound that has shown potential as a therapeutic for neurodegenerative disease*. Cross-sectional analyses of cognitively normal individuals aged 65-90yrs from the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohort were stratified by amyloid status (Aβ+, SUVR >1.35). Plasma ET, its metabolites and urinary allantoin, were quantified by liquid chr…

Perivascular Space Progression in Patients with Cerebral Amyloid Angiopathy.

INTRODUCTION: Dilated perivascular spaces (PVS) are associated with small vessel disease in the aging population. We sought to investigate the incidence and dynamic evolution of magnetic resonance imaging (MRI)-detectable PVS progression in patients with cerebral amyloid angiopathy (CAA). METHODS: Patients with symptomatic CAA who underwent baseline and follow-up MRI scans >2 years apart were included. The severity of both basal ganglia (BG) and centrum semiovale (CSO) PVS were rated. Multivariable logistic regression was used to determine the risk factors for PVS progression. RESULTS: We in…

Novel Amyloid-β Aggregation Inhibitors Based on Phenylalanine Structure.

INTRODUCTION/OBJECTIVE: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregation, making its inhibition a promising therapeutic strategy. This study evaluated the effects of two phenylalanine derivatives on Aβ aggregation and associated neurotoxicity. METHODS: Interactions between Aβ monomer and two compounds (12a and 5g) were explored by molecular docking. The inhibitory effects of the compounds on Aβ aggregation were evaluated using a thioflavin-T (ThT) assay, transmission electron microscopy (TEM), and dot blot. The neuroprotective ability of the two compounds was assessed u…

Reversible Rapidly Progressive Dementia Due to Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is a vascular disorder of the brain caused by beta-amyloid deposits in small- and medium-sized vessels. In some patients, the condition triggers an inflammatory response, which can appear in different forms based on the pattern of vessel involvement. These rare but treatable inflammatory variants may present with a syndrome of rapidly progressive dementia, which may pose a diagnostic challenge. Here, we describe a 76-year-old man who experienced two distinct episodes of rapidly progressive cognitive deterioration accompanied by diffuse weakness and seizure act…

Reversing Enamel Mineralization Inhibition Using Amyloid-like Protein Film.

Enamel remineralization holds considerable promise for dental caries, yet clinical translation remains hampered by the spontaneous deposition of acquired salivary pellicle (ASP), which passivates enamel surfaces and suppresses mineralization kinetics. Here, we present an ASP-repelling mineralization strategy based on a phase-transitioned bovine serum albumin (PTB) nanocoating fabricated via amyloid-like protein self-assembly. The PTB nanocoating confers robust antifouling properties that effectively inhibit ASP adsorption while simultaneously providing exceptional biomineralization activity. U…

Glucocerebrosidase rescues alpha-synuclein from amyloid formation in vitro.

Alpha-synuclein (αSyn) is a lipid-binding protein that assembles into amyloid fibrils in Parkinson's disease (PD). Lipid binding can accelerate the rate of αSyn fibril formation by stimulating primary nucleation. Recently, the lysosomal protein glucocerebrosidase (GCase) has been identified as a major risk factor in both genetic and sporadic PD. Using solution-state nuclear magnetic resonance spectroscopy, we observe that GCase binds to the C-terminal region of αSyn and attenuates the lipid-binding affinity of αSyn. Mechanistically, this interaction model involves competition between lipids an…

Transthyretin amyloid fibrils adopt distinct folds in the brain.

Amyloid deposition in the central nervous system is increasingly recognized in transthyretin (ATTR) amyloidosis, particularly in patients with prolonged survival following liver transplantation or disease-modifying therapies. However, the structural basis of transthyretin aggregation in the brain remains unknown. Here we determine cryo-electron microscopy (cryo-EM) structures of ex vivo brain-derived ATTR fibrils from patients carrying the ATTRv-V30M and ATTRv-V30G variants. Both fibrils adopt folds distinct from those previously reported in peripheral tissues and the vitreous humor. V30M fibr…

Post-Translational Isoaspartate Promotes Amyloid Formation in β2-Microglobulin.

β2-Microglobulin (β2m) aggregation is central to dialysis-related amyloidosis (DRA), yet the molecular triggers underlying its fibrillogenesis remain incompletely defined. Among proposed mechanisms, isoaspartate (isoAsp) formation at Asn residues has been implicated but never directly tested due to synthetic inaccessibility. Here, we report the total chemical synthesis of β2m variants containing isoAsp at known in vivo hotspots, Asn17 and Asn42, enabling precise structural and functional interrogation. Remarkably, the isoAsp17-modified β2m exhibited greater fibril formation capacity than the p…

A lattice Monte Carlo model for amyloid fibril formation.

Proteins can aggregate to form amyloid fibrils, which are associated with a group of diseases collectively known as amyloidoses. Molecular dynamics simulations are widely used to study protein aggregation; however, it remains computationally challenging to investigate the entire aggregation process, from initial nucleation to the formation of mature amyloid fibrils, within a single simulation. In this study, we propose a Monte Carlo simulation based on a mathematical lattice model in which proteins are represented as spheres on a lattice. Motivated by the role of intramolecular β-sheet structu…

Real-world outcomes of tafamidis in transthyretin amyloid cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive infiltrative cardiomyopathy associated with substantial morbidity and mortality. Although tafamidis has shown clinical benefit in randomized trials, real-world data are needed to contextualize outcomes in routine practice. OBJECTIVE: To describe baseline characteristics, extracardiac diagnostic red flags, and longitudinal outcomes in patients with ATTR-CM treated with tafamidis. METHOD: This retrospective, longitudinal, single-center study included consecutive patients with ATTR-CM who started tafamidis between July …

Evidence for progressive neurodegeneration in iatrogenic cerebral amyloid angiopathy.

INTRODUCTION: Iatrogenic transmission of amyloid beta can cause cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), but the relationship between these phenotypes is unclear. METHODS: We retrospectively analyzed standardized neuropsychological and neuroimaging data from 11 patients with iatrogenic CAA (iCAA). Brain MRI was assessed for medial temporal lobe atrophy (MTA), the posterior atrophy score for parietal atrophy, and global cortical atrophy (GCA). RESULTS: All patients (mean age 42 ± 8.3 years) had childhood neurosurgery; 91% had confirmed cadaveric dura exposure. Six patie…

Diagnostic discordance in amyloidosis: lessons from proteomic amyloid typing.

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… Proteomic amyloid typing by mass spectrometry (MS) is increasingly considered the reference standard for amyloid classification because of its high sensitivity and specificity, especially when compared to conventional techniques such as immunofluorescence (IF) and immunohistochemistry (IHC) [ 3 , 4 ] … Patient 5: a 78-year-old man with IgA κ multiple myeloma and severe acute kidney injury requiring dialysis had amyloid deposits identified on abdominal fat biopsy. MS demonstrated AL λ amyloid, highlighting discordance between the detected plasma cell clone and the amyloid subtype. …

Revisiting Alzheimer's Disease Mechanisms: Amyloid Dynamics, and Emerging Insights.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by synaptic dysfunction, glial cell activation, and deterioration of neurons. Multiple pathways contribute to its pathophysiology, including β-amyloid (Aβ) plaque formation, intracellular neurofibrillary tangles, oxidative neuronal damage, and inflammatory responses. While Aβ deposition is considered an early trigger in the disease cascade, clinical symptom progression correlates more strongly with tau pathology and inflammatory responses. Recent concerns over data integrity in several high-profile AD studies have prom…

Efficient amyloid-β degradation in Alzheimer's disease using SPYTACs.

Clearance of aberrant cerebral amyloid-β (Aβ) deposits represents a promising therapeutic strategy for Alzheimer's disease (AD), yet current anti-Aβ immunotherapy raises safety concerns due to frequent adverse effects. Extracellular targeted protein degradation (eTPD) offers an approach for safe and efficient clearance of disease-causing proteins. Here, we develop a next-generation eTPD platform, synthetic peptide-programmed lysosome-targeting chimeras (SPYTACs), using entirely synthesized bispecific peptides. Leveraging low-density lipoprotein receptor-related protein 1 (LRP1), SPYTACs effect…

6-gingerol interferes with amyloid-beta (Aβ) peptide aggregation.

Alzheimer's disease (AD) is the most prevalent age-related cause of dementia. AD affects millions of people worldwide, and to date there is no cure. The pathological hallmark of AD brains is deposition of amyloid plaques, which mainly consist of amyloid-β (Aβ) peptides, commonly 40 or 42 residues long, that have aggregated into amyloid fibrils. Intermediate aggregates in the form of soluble Aβ oligomers appear to be highly neurotoxic. Cell and animal studies on mice have previously demonstrated positive effects of the molecule 6-gingerol on AD pathology. Gingerols are the main active constitue…

The elusive relationship between retinal anatomy and brain amyloid.

This scientific commentary refers to 'Retinal microstructure and microvasculature in association with brain amyloid burden', by Egle et al. (https://doi.org/10.1093/braincomms/fcaf013).

Microglial Clearance of Alzheimer's Amyloid-Beta Obstructed by Nanoplastics.

Understanding the neurological impact of nanoplastic exposure has become an area of intensive research recently. This study examined the molecular and cellular mechanisms of how nanoplastics affect amyloid-beta (Aβ) clearance by microglia in the context of Alzheimer's disease (AD). Transmission electron microscopy and molecular dynamics simulations showed that polystyrene nanoplastics accelerated Aβ aggregation by forming a protein corona, promoting peptide fibrillization through hydrogen bonding and π-π interactions. Flow cytometry and endocytosis inhibition assays revealed that polystyrene n…