Degradation of amyloid β-peptides catalyzed by nattokinase in vivo and in vitro

Amyloid-β 1-42(Aβ42)plays a pivotal role in Alzheimer disease(AD)pathogenesis. Peripheral clearance of Aβ42 largely affects its level in the brain and affects AD progression. Although nattokinase(NK)degrades Aβ40, the details of NK's capture of various Aβ species and reduction of plasma Aβ42/Aβ40 are uncharacterized. In this study, the Aβ42/Aβ40-degrading ability of NK was investigated using five Aβs and AD model mice. The C-terminal region of Aβ42/Aβ40(Gly29 to Val40)was primarily required for NK capture, and the integrated conformation in Aβ42/Aβ40 aggregates was a more efficient target for NK catalysis. Further, suspended Aβ42/Aβ40 oligomers were more easily captured by NK than suspended Aβ42/Aβ40 fibrils, while deposited Aβ42/Aβ40 fibrils recruited more NK than deposited Aβ42/Aβ40 oligomers. Although most NK was likely lost during NK uptake and/or entry into the blood, a small fraction of NK showed good plasma Aβ42/Aβ40-degrading efficacy after entering the blood due to NK's stability in the plasma of AD mice for at least 9 days. It was concluded that oral administration of NK is a feasible approach for peripheral Aβ42/Aβ40 clearance. This implies that NK might serve as an anti-Aβ42 agent for the treatment of Aβ42/Aβ40-related diseases such as AD.

Molecular dynamics studies of the inhibitory mechanism of copper(Ⅱ) on aggregation of amyloid β-peptide

The inhibitory mechanism of copper（Ⅱ） on the aggegation of amyloid β-peptide （Aβ） was investigated by molecular dynamics simulations. The binding mode ofcopper（Ⅱ） with Aβ is characterized by the imidazole nitrogen atom, Nπ, of the histidine residue H 13, acting as the anchoring site, and the backbone＇s deprotoned amide nitogen atoms as the main binding sites. Drove by the coordination bonds and their induced hydrogen bond net, the conformations of Aβ converted from β-sheet non-β-sheet conformations, which destabilized the aggregation of Aβ into fibrils.

Amyloid β and free heme：bloody new insights into the pathogenesis of Alzheimer＇s disease

The cerebral formation of Amyloid β（Aβ） is a critical pathological feature of Alzheimer＇s disease（AD）.An accumulation of this peptide as senile plaques（SP） was already reported by Alois Alzheimer,the discoverer of the disease.Yet the exact contribution of Aβ to AD development remains elusive.Moreover,while extensive cerebral Aβ formation leads to fibril formation in many species,AD-like symptoms apparently depend on the highly conserved N-terminal residues R5,Y10 and H13.The amino acids were also shown to lead to the formation of Aβ-heme complexes,which exhibit peroxidase activity in the presence of H_2O_2.Taking together these observations we propose that the formation and enzymatic activity of the named complexes may represent an essential aspect of AD pathology.Furthermore,Aβ is also known to lead to cerebral micro-vessel destruction（CAA） as well as to hemolytic events.Thus we suggest that the Aβ-derived cerebral accumulation of blood-derived free heme represents a likely precondition for the subsequent formation of Aβ-heme complexes.

A predictive,simple and rapid method for thermodynamic study on the binding of copper ion with Alzheimer's amyloid β peptide

The interaction of CuCl2 to the first 16 residues of the Alzheimer＇s amyliod β peptide, Aβ（1-16） was studied by isothermal titration calorimetry at pH 7.2 and 37℃ in aqueous solution.

Neuroprotective effects of statins against amyloid β-induced neurotoxicity

A growing body of evidence suggests that disruption of the homeostasis of lipid metabolism affects the pathogenesis of Alzheimer＇s disease （AD）. In particular, dysregulation of cholesterol homeostasis in the brain has been reported to considerably increase the risk of developing AD. Thus, dysregulation of lipid homeostasis may increase the amyloid β （Aβ） levels by affecting amyloid precursor protein （APP） cleavage, which is the most important risk factor involved in the pathogenesis of AD. Previous research demonstrated that Aβ can trigger neuronal insulin resistance, which plays an important role in response to Aβ-induced neurotoxicity in AD. Epidemiological studies also suggested that statin use is associated with a decreased incidence of AD. Therefore, statins are believed to be a good candidate for conferring neuropro- tective effects against AD. Statins may play a beneficial role in reducing A^-induced neurotoxicity. Their effect involves a putative mechanism beyond its cholesterol-lowering effects in preventing A[3-induced neurotoxicity. However, the underlying molecular mechanisms of the protective effect of statins have not been clearly determined in Aβ-induced neurotoxicity. Given that statins may provide benefits beyond the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A （HMG-CoA） reductase, these drugs may also improve the brain. Thus, statins may have beneficial effects on impaired insulin signaling by activating AMP-activated protein kinase （AMPK） in neuronal cells. They play a potential therapeutic role in targeting Aβ-mediated neurotoxicity.

Evaluation of the inhibitory effect of docosahexaenoic acid and arachidonic acid on the initial stage of amyloid β1-42 polymerization by fluorescence correlation spectroscopy

Amyloid β(Aβ)1-42 fibrillation is a crucial step in the development of pathological hallmarks, such as neuritic plaques and neurofibrillary tangles, of Alzheimer’s disease (AD). In this study, we evaluated the effects of free docosahexaenoic acid (DHA), an essential brain polyunsaturated fatty acid (PUFA), on the inhibition of Aβ1-42 fibrillation by fluorescence correlation spectroscopy (FCS), a technique capable of detecting molecular movements and interactions in solution. We also examined whether free arachidonic acid (AA), eicosapentaenoic acid (EPA), and metabolites of DHA, including neuroprotectin D1 (NPD1, 10S, 17S-dihydroxy-DHA), resolvin D1 (RvD1, 7S, 8R, 17S-trihydroxy-DHA), and didocosahexaenoyl glycerol (diDHA), affect Aβ1-42 polymerization. The results of the FCS study reveal that DHA and AA significantly reduced the diffusion time of TAMRA (5-carboxytetramethylrhoda-mine)-Aβ1-42 by 28% and 31%, respectively, while EPA, NPD1, RvD1, and diDHA had no effects on diffusion time. These results indicate that DHA and AA inhibited Aβ1-42 polymerization and that their inhibitory effects occurred at the initial stage of Aβ1-42 polymerization. This study will advance the research on PUFAs in preventing AD progression.

Cholinergic receptor, nicotinic, alpha 7 as a target molecule of Arctic mutant amyloid β

Alzheimer’s disease（AD）is a progressive cognitive disorder that develops predominantly in elderly patients and is characterized by cognitive impairments affecting memory,learning,and attention（Selkoe,2002）.

CSF tau and amyloid β₄₂levels in Alzheimer’s disease—A meta-analysis

Alzheimer’s disease International (ADI) estimates that there are currently 30 million people with dementia in the world. The main objective was to perform meta-analysis of studies of CSF tau and Amyloid β42 (Aβ42) levels in Alzheimer’s disease (AD) patients and controls. In the present study MEDLINE was reviewed from 1995 to 2009, supplemented by citation analysis from retrieved articles to select case control studies. Descriptive statistics showed that median effect size (raw mean difference) of CSF tau and Aβ42 levels were 301 pg/ml (Range: 22 to 614 pg/ml) and –352 pg/ml (Range: –969 to 203 pg/ml) respectively. The pooled effect size CSF tau and Aβ42 was 289.14 pg/ml (95% CI 253.278 to 325.013 pg/ml) and –329.02 pg/ml (95% CI –387.740 to –270.445 pg/ml) respectively. Heterogeneity in effect size of selected studies was present for both parameters (CSF tau: Q statistics = 1816.596, DF = 40, P = 0.000 and CSF Aβ42: Q-statistics = 1259.358, DF = 24, p 42 levels in AD and controls may be considered as potential biomarker along with the clinical phenotype to perform them during high quality diagnostic testing in dementia.

Current perspective on amyloid aggregation accelerating properties of the artificial butter flavoring,diacetyl

The amyloid—what peptide can resist its entropic bliss?Without kinetic barricades and chaperones,most peptides would simply tumble down that precipice.The amyloid-β(Aβ) peptides are understood to underlie the hallmark pathology of Alzheimer's disease(AD) and are considered one of the causative factors for neurodegeneration and cognitive impairment.AD affects critical connected structures within the brain that are responsible for memory,language,and social behavior.

Transmission of amyloid-βpathology in humans:a perspective on clinical evidence

Transmission of misfolded amyloid-β(Aβ)aggregates between human subjects:Protein misfolding disorders are a family of diseases characterized by the accumulation of misfolded protein aggregates.These proteinaceous structures,also known as amyloids,are key drivers of fatal neurodegenerative disorders such as prion diseases,Alzheimer’s disease(AD),Parkinson’s disease,and others.

Medin synergized with vascular amyloid-beta deposits accelerates cognitive decline in Alzheimer's disease:a potential biomarker

Brain vascular dysfunction in Alzheimer s disease(AD) pathogenesis has become increasingly clea r.Accumulating evidence shows that damaged vascular,including large or small vessels and even neurovascular unit,may accelerate the neuropathological process of AD via disrupting brain hypoperfusion,aberrant angiogenesis,and neuroinflammatory response,etc.Thus,vascular dysfunction makes a substantially contribution to the cognitive decline of AD patients.

Anti-amyloid antibodies in Alzheimer’s disease: what did clinical trials teach us?

Although many causes of Alzheimer’s disease(AD)may exist,both the original amyloid cascade and tau hypotheses posit that abnormal misfolding and accumulation of amyloid-β(Aβ)and tau protein is the central event causing the pathology.However,that conclusion could be only partly true,and there is conflicting evidence about the role of both proteins in AD,being able to precede and influence one another.Some researchers argue that these proteins are mere executors rather than primary causes of pathology.Therefore,there have been continuing refinements of both hypotheses,with alternative explanations proposed.Aβand tau proteins may be independently involved in specific neurotoxic pathways;yet there may be other crucial processes going on in early AD.Moreover,accumulating evidence suggests that Aβand tau act synergistically,rather than additively in disease onset(Jeremic et al.,2021,2023a).

Design and redesign journey of a drug for transthyretin amyloidosis

The misfolding and subsequent aggregation of proteins into amyloid fibrils underlie the onset of a variety of human disorders collectively known as amyloidosis.Transthyretin(TTR)is one of the>30 amyloidogenic proteins identified to date and is associated with a group of highly debilitating and life-threatening disorders called TTR amyloidosis(ATTR).ATTR comprises senile systemic amyloidosis,which is linked to wild-type(WT)TTR aggregation,and hereditary ATTR,a dominantly inherited disorder caused by the deposition of one of over 130 TTR genetic variants.Senile systemic amyloidosis is a prevalent age-related amyloidosis,affecting up to 25%of the population over 80 years of age,and is characterized by the build-up of TTR fibrils in the myocardium.Regarding hereditary ATTR,the clinical presentation is highly heterogeneous,primarily affecting the peripheral nervous system(familial amyloid polyneuropathy-FAP)or the heart(familial amyloid cardiomyopathy).In rare cases,aggregation develops in the central nervous system,giving rise to a phenotype known as familial leptomeningeal amyloidosis(Carroll et al.,2022).

Management of cerebral amyloid angiopathy and atrial fibrillation:We are still far from precision medicine

The use of anticoagulation therapy could prove to be controversial when trying to balance ischemic stroke and intracranial bleeding risks in patients with concurrent cerebral amyloid angiopathy(CAA)and atrial fibrillation(AF).In fact,CAA is an age-related cerebral vasculopathy that predisposes patients to intracerebral hemorrhage.Nevertheless,many AF patients require oral systemic dose-adjusted warfarin,direct oral anticoagulants(such as factor Xa inhibitors)or direct thrombin inhibitors to control often associated with cardioembolic stroke risk.The prevalence of both CAA and AF is expected to rise,due to the aging of the population.This clinical dilemma is becoming increasingly common.In patients with coexisting AF and CAA,the risks/benefits profile of anticoagulant therapy must be assessed for each patient individually due to the lack of a clear-cut consensus with regard to its risks in scientific literature.This review aims to provide an overview of the management of patients with concomitant AF and CAA and proposes the implementation of a risk-based decision-making algorithm.

Recurrent Transient Ischemic Attacks Revealing Cerebral Amyloid Angiopathy: A Comprehensive Case

This case report investigates the manifestation of cerebral amyloid angiopathy (CAA) through recurrent Transient Ischemic Attacks (TIAs) in an 82-year-old patient. Despite initial diagnostic complexities, cerebral angiography-MRI revealed features indicative of CAA. Symptomatic treatment resulted in improvement, but the patient later developed a fatal hematoma. The discussion navigates the intricate therapeutic landscape of repetitive TIAs in the elderly with cardiovascular risk factors, emphasizing the pivotal role of cerebral MRI and meticulous bleeding risk management. The conclusion stresses the importance of incorporating SWI sequences, specifically when suspecting a cardioembolic TIA, as a diagnostic measure to explore and exclude CAA in the differential diagnosis. This case report provides valuable insights into these challenges, highlighting the need to consider CAA in relevant cases.

The expanding amyloid family:Structure,stability,function,and pathogenesis

The hidden world of amyloid biology has suddenly snapped into atomic-level focus,revealing over 80 amyloid protein fibrils,both pathogenic and functional.Unlike globular proteins,amyloid proteins flatten and stack into unbranched fibrils.Stranger still,a single protein sequence can adopt wildly different two-dimensional conformations,yielding distinct fibril polymorphs.

Plasma amyloid-beta oligomer and phosphorylated tau:diagnostic tools for progressive Alzheimer's disease

Introduction:Spanning the three stages of the Alzheimer’s disease (AD) continuum,amyloid-beta(Aβ40and Aβ42) oligomers (AβO’s) and tau protein constitute a set of biomarkers ideally suited for the non-invasive monitoring of AD (Wolgin et al.,2022).AD progression is correlated with the presence of low molecular weight oligomers and not amyloid plaques.Moreover,low molecular weight AβO is present in the beginning and later stages of disease even when the plaque burden becomes prevalent.Furthermore.

A pancreatic player in dementia:pathological role for islet amyloid polypeptide accumulation in the brain

Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes mellitus.Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear.In this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of dementia.We discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced cytotoxicity.There are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at best.Therefore,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating dementia.As such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.

Enhancing the compatibility of the amyloid-dye hybrid nanostructure for improved photo-biocatalysis

Artificial photosynthesis is significant for renewable energy generation,sustainable development,and environmental protection.Dye-protein hybrids are promising for developing photosynthesis mimics(e.g.,photo-biocatalysis),but their performances are far lower than the plant photosystems,partially because of the incompatibility between dye and the protein matrix that limits excited state electron transfer of the included dyes.Here,using ThT-insulin amyloid assembly as a model system,we proposed that increasing the dye-protein compatibility could lead to the improved photo-biocatalytic performance.A ThT derivative,ThTPD,was designed with the same electron acceptor but extended π-conjugated donor structure.When integrated into the insulin amyloid,the extended π-conjugated donor structure allowed increased binding affinity and energy with the amyloid matrix,thus better electron transport to the mediator to drive the photocatalytic reaction.Meanwhile,compared with ThT, ThTPD exhibited improved light absorption and longer excited state lifetime.The photo-biocatalytic performance of ThTPD-insulin amyloid was greatly improved as compared with that of ThT in reduced nicotinamide adenine dinucleotide(NADH) regeneration.When integrating with NADH-dependent L-glutamate reductase,the efficiency of the ThTPD-insulin amyloid hybrid was 2.8-fold higher than that of ThT in glutamate generation,showing promising feature in biocatalytic solar-to-chemical conversion.

The tip of the iceberg?The underestimated potential of non-canonical beta-amyloids for Alzheimer's disease

Formation and deposition of amyloid-beta(Aβ) are considered one of the main drivers of Alzheimer's disease(AD). For more than 30 years, Aβ has challenged researchers through its complex physicochemical properties and multiple peptide processing steps that involve several proteases(Andreasson et al., 2007).