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,...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.展开更多
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 hallm...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.展开更多
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 st...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.展开更多
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 acce...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.展开更多
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 ang...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.展开更多
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 int...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.展开更多
Neuroinflammation has been recognized to play a critical role in the pathogenesis of Alzheimer's disease (AD), which is pathologically characterized by the accumulation of senile plaques containing activated micro...Neuroinflammation has been recognized to play a critical role in the pathogenesis of Alzheimer's disease (AD), which is pathologically characterized by the accumulation of senile plaques containing activated microglia and amyloid β-peptides (Aβ). In the present study, we examined the neuroprotective effects of hydrogen sulfide (H2S) on neuroinflammation in rats with Aβ1-40 hippocampal injection. We found that Aβ-induced rats exhibited a disorder of pyramidal cell layer arrangement, and a decrease of mean pyramidal cell number in the CA1 hippocampal region compared with those in sham operated rats. NaHS (a donor of H2S, 5.6 mg/kg/d, i.p.) treatment for 3 weeks rescued neuronal cell death significantly. Moreover, we found that H2S dramatically suppressed the release of TNF-α, IL-1β and IL-6 in the hippocampus. Consistently, both immunohistochemistry and Western blotting assays showed that H2S inhibited the upregulation of COX-2 and the activation of NF-κB in the hippocampus. In conclusion, our data indicate that H2S suppresses neuroinflammation via inhibition of the NF-κB activation pathway in the Aβ-induced rat model and has potential value for AD therapy.展开更多
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 mon...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.展开更多
The inhibitory mechanism of copper(Ⅱ) on the aggregation of amyloid β-peptide (Aβ) was investigated by molecular dynamics simulations.The bindingmode ofcopper(Ⅱ) with Aβ is characterized by the imidazolenitrogena...The inhibitory mechanism of copper(Ⅱ) on the aggregation of amyloid β-peptide (Aβ) was investigated by molecular dynamics simulations.The bindingmode ofcopper(Ⅱ) with Aβ is characterized by the imidazolenitrogenatom,Nπ, of the histidine residue H13,acting as the anchoring site, and the backbone's deprotoned amide nitrogen 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.展开更多
Cannabidiol (CBD), one of the most studied phytocannabinoids, is non-psychotropic and can induce protective effects on the central nervous system against acute and chronic brain injury. Interestingly, CBD inhibits pro...Cannabidiol (CBD), one of the most studied phytocannabinoids, is non-psychotropic and can induce protective effects on the central nervous system against acute and chronic brain injury. Interestingly, CBD inhibits processes relating to amyloid beta (Aβ)-induced neurotoxicity in mouse models of Alzheimer’s disease, though the detailed molecular mechanism underlying the CBD neurotoxicity modulation is not fully understood. In this study, using atomic force microscopy, we find that CBD promotes the aggregation of Aβ peptides, enhancing the formation of Aβ oligomers, also known as Aβ-derived diffusible ligands (ADDLs). The CBD-mediated sequestration of Aβ monomers in soluble ADDLs could reduce neurotoxicity. This study highlights a possible role of CBD in modulating the formation of ADDL aggregates and provides insight into potentially neuroprotective properties of CBD in Alzheimer’s disease.展开更多
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 po...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.展开更多
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 propertie...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).展开更多
Scutellaria baicalensis stem-leaf total flavonoid might attenuate learning/memory impairment and neuronal loss in rats induced by amyloid beta-peptide. This study aimed to explore the effects of Scutellaria baicalensi...Scutellaria baicalensis stem-leaf total flavonoid might attenuate learning/memory impairment and neuronal loss in rats induced by amyloid beta-peptide. This study aimed to explore the effects of Scutellaria baicalensis stem-leaf total flavonoid on amyloid beta-peptide-induced neuronal apoptosis and the expression of apoptosis-related proteins in the rat hippocampus. Male Wistar rats were given intragastric administration of Scutellaria baicalensis stem-leaf total flavonoid, 50 or 100 mg/kg, once per day. On day 8 after administration, 10 μg amyloid beta-peptide (25-35) was injected into the bilateral hippocampus of rats to induce neuronal apoptosis. On day 20, hippocampal tissue was harvested and probed with the terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick-end labeling assay. Scutellaria baicalensis stem-leaf total flavonoid at 50 and 100 mg/kg reduced neuronal apoptosis induced by amyloid beta-peptide (25-35 in the rat hippocampus. Immunohistochemistry and western blot assay revealed that expression of the pro-apoptotic protein Bax, cytochrome c and caspase-3 was significantly diminished by 50 and 100 mg/kg Scutellaria baicalensis stem-leaf total flavonoid, while expression of the anti-apoptotic protein Bcl-2 was increased. Moreover, 100 mg/kg Scutellaria baicalensis stem-leaf total flavonoid had a more dramatic effect than the lower dosage. These experimental findings indicate that Scutellaria baicalensis stem-leaf total flavonoid dose-dependently attenuates neuronal apoptosis induced by amyloid beta-peptide in the hippocampus, and it might mediate this by regulating the expression of Bax, cytochrome c, caspase-3 and Bcl-2.展开更多
Cardiac amyloidosis(CA)is caused by deposition of amyloid fibrils in the myocardium and has two main sub-types,transthyretin cardiac amyloidosis(ATTR)and immunoglobulin light chain cardiac amyloidosis(AL).ATTR is furt...Cardiac amyloidosis(CA)is caused by deposition of amyloid fibrils in the myocardium and has two main sub-types,transthyretin cardiac amyloidosis(ATTR)and immunoglobulin light chain cardiac amyloidosis(AL).ATTR is further dif-ferentiated into wild-type(wtATTR)and hereditary(hATTR),depending on the absence or presence of mutation in the trans-thyretin gene.The increased recognition of disease with the improvement in diagnostic armamentarium and serendipitous ad-vancements in the therapeutic landscape have changed the status of CA from being a rare and untreatable disease to being a not-so-rare and treatable disease.Both ATTR and AL have certain clinical aspects that can provide early clues for the disease.While electrocardiography followed by echocardiography and subsequently cardiac magnetic resonance can raise suspicion for CA,the definitive diagnosis of ATTR is non-invasively established by bone scintigraphy while that of AL always needs histological con-firmation.Severity of CA can be gauged by serum biomarker-based staging of both ATTR and AL.ATTR therapies work by silen-cing or stabilizing TTR or by degrading amyloid fibrils,while AL is managed with anti-plasma cell therapies and autologous stem cell transplant.展开更多
Protein misfolding and aggregation into amyloid fibrils is the main pathological hallmark of neurodegenerative diseases,including Alzheimer’s,Parkinson’s,Huntington’s,and prion diseases(Chiti and Dobson,2017).These...Protein misfolding and aggregation into amyloid fibrils is the main pathological hallmark of neurodegenerative diseases,including Alzheimer’s,Parkinson’s,Huntington’s,and prion diseases(Chiti and Dobson,2017).These insoluble fibrillar deposits possess a common structure characterized by a cross-β-sheet conformation in which β-strands run transversely to the fiber axis and form an intermolecular network of hydrogen bonds.展开更多
Amyloid β-peptide,a major component of senile plaques in Alzheimer’s disease,has been implicated in neuronal cell death and cognitive impairment.Recently,studies have shown that the pathogenesis of cerebral ischemia...Amyloid β-peptide,a major component of senile plaques in Alzheimer’s disease,has been implicated in neuronal cell death and cognitive impairment.Recently,studies have shown that the pathogenesis of cerebral ischemia is closely linked with Alzheimer’s disease.In this study,a rat model of global cerebral ischemia-reperfusion injury was established via occlusion of four arteries;meanwhile,fibrillar amyloidβ-peptide was injected into the rat lateral ventricle.The Morris water maze test and histological staining revealed that administration of amyloidβ-peptide could further aggravate impairments to learning and memory and neuronal cell death in the hippocampus of rats subjected to cerebral ischemia-reperfusion injury.Western blot showed that phosphorylation of tau protein and the activity of glycogen synthase kinase 3βwere significantly stronger in cerebral ischemia-reperfusion injury rats subjected to amyloid β-peptide administration than those undergoing cerebral ischemia-reperfusion or amyloidβ-peptide administration alone.Conversely,the activity of protein phosphatase 2A was remarkably reduced in rats with cerebral ischemia-reperfusion injury following amyloidβ-peptide administration.These findings suggest that amyloidβ-peptide can potentiate tau phosphorylation induced by cerebral ischemia-reperfusion and thereby aggravate cognitive impairment.展开更多
Potential causes for the clinical and pathological variability observed in Alzheimer’s disease(AD):AD is an age-related neurodegenerative disorder characterized by the impairment of cognitive functions such as memory...Potential causes for the clinical and pathological variability observed in Alzheimer’s disease(AD):AD is an age-related neurodegenerative disorder characterized by the impairment of cognitive functions such as memory,learning,and reasoning.These commonly described clinical symptoms are due to particular pathological changes in the brain,including inflammation,synaptic loss,and neuronal death.These changes are a consequence of the accumulation of abnormally folded amyloid-β(Aβ)and tau proteins in specific areas of the central nervous system.Considering the progressive aging of the world’s population,the number of people affected by AD is expected to substantially and consistently increase in the coming years.This positions AD as one of the main public health challenges in the near future.展开更多
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-biocataly...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.展开更多
Nickel,an important transi-tion metal element,is one of the trace elements for hu-man body and has a crucial impact on life and health.Some evidences show the excess exposure to metal ions might be associated with neu...Nickel,an important transi-tion metal element,is one of the trace elements for hu-man body and has a crucial impact on life and health.Some evidences show the excess exposure to metal ions might be associated with neurological diseases.Herein,we applied Raman spectroscopy to study the Ni(II)ion effect on kinetics of amyloid fibrillation of hen egg white lysozyme(HEWL)in thermal and acidic conditions.Using the well-known Raman indicators for protein tertiary and secondary structures,we monitored and analyzed the concentration effect of Ni(II)ions on the unfolding of tertiary structures and the transformation of sec-ondary structures.The experimental evidence validates the accelerator role of the metal ion in the kinetics.Notably,the additional analysis of the amide I band profile,combined with thioflavin-T fluorescence assays,clearly indicates the inhibitory effect of Ni(II)ions on the formation of amyloid fibrils with organizedβ-sheets structures.Instead,a more significant promotion influence is affirmed on the assembly into other aggregates with disordered struc-tures.The present results provide rich information about the specific metal-mediated protein fibrillation.展开更多
BACKGROUND Islet amyloid deposition and reducedβ-cell mass are pathological hallmarks in type 2 diabetes mellitus subjects.To date,the pathological features of the islets in diabetes secondary to pancreatic ductal ad...BACKGROUND Islet amyloid deposition and reducedβ-cell mass are pathological hallmarks in type 2 diabetes mellitus subjects.To date,the pathological features of the islets in diabetes secondary to pancreatic ductal adenocarcinoma(PDAC)have not been specifically addressed.AIM To provide further insight into the relationship between islet amyloid deposition of the residual pancreas in PDAC patients and to explore whether regional differences(proximal vs distal residual pancreas)are associated with islet amyloid deposition.METHODS We retrospectively collected clinical information and pancreatic tissue removed from tumors of 45 PDAC patients,including 14 patients with normal glucose tolerance(NGT),16 patients with prediabetes and 15 new-onset diabetes(NOD)patients diagnosed before surgery by an oral glucose tolerance test at West China Hospital from July 2017 to June 2020.Pancreatic volume was calculated by multiplying the estimated area of pancreatic tissue on each image slice by the interval between slices based on abdominal computer tomography scans.Several sections of paraffin-embedded pancreas specimens from both the proximal and/or distal regions remote from the tumor were stained as follows:(1)Hematoxylin and eosin for general histological appearance;(2)hematoxylin and insulin for the determination of fractionalβ-cell area(immunohistochemistry);and(3)quadruple insulin,glucagon,thioflavin T and DAPI staining for the determination ofβ-cell area,α-cell area and amyloid deposits.RESULTS Screening for pancreatic histologic features revealed that duct obstruction with islet amyloid deposition,fibrosis and marked acinar atrophy were robust in the distal pancreatic regions but much less robust in the proximal regions,especially in the prediabetes and NOD groups.Consistent with this finding,the remnant pancreatic volume was markedly decreased in the NOD group by nearly one-half compared with that in the NGT group(37.35±12.16 cm^(3) vs 69.79±18.17 cm^(3),P<0.001).As expected,islets that stained positive for amyloid(islet amyloid density)were found in the majority of PDAC cases.The proportion of amyloid/islet area(severity of amyloid deposition)was significantly higher in both prediabetes and NOD patients than in NGT patients(P=0.002;P<0.0001,respectively).We further examined the regional differences in islet amyloid deposits.Islet amyloid deposit density was robustly increased by approximately 8-fold in the distal regions compared with that in the proximal regions in the prediabetes and NOD groups(3.98%±3.39%vs 0.50%±0.72%,P=0.01;12.03%vs 1.51%,P=0.001,respectively).CONCLUSION In conclusion,these findings suggest that robust alterations of the distal pancreas due to tumors can disturb islet function and structure with islet amyloid formation,which may be associated with the pathogenesis of NOD secondary to PDAC.展开更多
基金supported by the National Natural Science Foundation of China Program (No. 31970883)。
文摘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.
基金supported by the National Institutes of Health Grant (R01-AG062469)the Grantin-Aid of Research,Artistry,Scholarship program (GIA,Project 143977) at the University of Minnesotafunding from the Center for Drug Design (CDD),University of Minnesota (to SSM)。
文摘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.
基金supported by grants from the Alzheimer’s Association(AARGD-18-566576)NIH/NIA(RF1AG072491)NIH/NIAID(R01AI132695)to RM。
文摘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.
基金supported by the Science and Technology Innovation 2030-Major Projects,No.2022ZD021 1 600the National Natural Science Foundation of China,Nos.82271574 and82071204 (all to CX)。
文摘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.
文摘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.
文摘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.
基金supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions(No.Jx10131801095 to HongZhou)
文摘Neuroinflammation has been recognized to play a critical role in the pathogenesis of Alzheimer's disease (AD), which is pathologically characterized by the accumulation of senile plaques containing activated microglia and amyloid β-peptides (Aβ). In the present study, we examined the neuroprotective effects of hydrogen sulfide (H2S) on neuroinflammation in rats with Aβ1-40 hippocampal injection. We found that Aβ-induced rats exhibited a disorder of pyramidal cell layer arrangement, and a decrease of mean pyramidal cell number in the CA1 hippocampal region compared with those in sham operated rats. NaHS (a donor of H2S, 5.6 mg/kg/d, i.p.) treatment for 3 weeks rescued neuronal cell death significantly. Moreover, we found that H2S dramatically suppressed the release of TNF-α, IL-1β and IL-6 in the hippocampus. Consistently, both immunohistochemistry and Western blotting assays showed that H2S inhibited the upregulation of COX-2 and the activation of NF-κB in the hippocampus. In conclusion, our data indicate that H2S suppresses neuroinflammation via inhibition of the NF-κB activation pathway in the Aβ-induced rat model and has potential value for AD therapy.
基金National Research Foundation of Korea (NRF) by the Korean Government (2020R1A2B5B01002463&2021R1A6A1A03038996)(to JPH)。
文摘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.
基金This work was supported by the National Natural Science Foundation of China(Nos.30470408 and 20637010).
文摘The inhibitory mechanism of copper(Ⅱ) on the aggregation of amyloid β-peptide (Aβ) was investigated by molecular dynamics simulations.The bindingmode ofcopper(Ⅱ) with Aβ is characterized by the imidazolenitrogenatom,Nπ, of the histidine residue H13,acting as the anchoring site, and the backbone's deprotoned amide nitrogen 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.
文摘Cannabidiol (CBD), one of the most studied phytocannabinoids, is non-psychotropic and can induce protective effects on the central nervous system against acute and chronic brain injury. Interestingly, CBD inhibits processes relating to amyloid beta (Aβ)-induced neurotoxicity in mouse models of Alzheimer’s disease, though the detailed molecular mechanism underlying the CBD neurotoxicity modulation is not fully understood. In this study, using atomic force microscopy, we find that CBD promotes the aggregation of Aβ peptides, enhancing the formation of Aβ oligomers, also known as Aβ-derived diffusible ligands (ADDLs). The CBD-mediated sequestration of Aβ monomers in soluble ADDLs could reduce neurotoxicity. This study highlights a possible role of CBD in modulating the formation of ADDL aggregates and provides insight into potentially neuroprotective properties of CBD in Alzheimer’s disease.
基金supported by The Mike Hogg FundBaylor College of Medicine Medical Scientist Training Program,NICHD R01HD099252(to RJP)and R01HD098131(to RJP)the NHLBI T32 HL092332(to ASB)。
文摘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.
基金Ministerium für Wissenschaft und Gesundheit (MWG),Rheinland Pfalz,Neurodeg X Forschungskolleg (to BB)。
文摘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).
基金supported by grants from Hebei Provincial Science and Technology Bureau,No.08276101D-21
文摘Scutellaria baicalensis stem-leaf total flavonoid might attenuate learning/memory impairment and neuronal loss in rats induced by amyloid beta-peptide. This study aimed to explore the effects of Scutellaria baicalensis stem-leaf total flavonoid on amyloid beta-peptide-induced neuronal apoptosis and the expression of apoptosis-related proteins in the rat hippocampus. Male Wistar rats were given intragastric administration of Scutellaria baicalensis stem-leaf total flavonoid, 50 or 100 mg/kg, once per day. On day 8 after administration, 10 μg amyloid beta-peptide (25-35) was injected into the bilateral hippocampus of rats to induce neuronal apoptosis. On day 20, hippocampal tissue was harvested and probed with the terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick-end labeling assay. Scutellaria baicalensis stem-leaf total flavonoid at 50 and 100 mg/kg reduced neuronal apoptosis induced by amyloid beta-peptide (25-35 in the rat hippocampus. Immunohistochemistry and western blot assay revealed that expression of the pro-apoptotic protein Bax, cytochrome c and caspase-3 was significantly diminished by 50 and 100 mg/kg Scutellaria baicalensis stem-leaf total flavonoid, while expression of the anti-apoptotic protein Bcl-2 was increased. Moreover, 100 mg/kg Scutellaria baicalensis stem-leaf total flavonoid had a more dramatic effect than the lower dosage. These experimental findings indicate that Scutellaria baicalensis stem-leaf total flavonoid dose-dependently attenuates neuronal apoptosis induced by amyloid beta-peptide in the hippocampus, and it might mediate this by regulating the expression of Bax, cytochrome c, caspase-3 and Bcl-2.
文摘Cardiac amyloidosis(CA)is caused by deposition of amyloid fibrils in the myocardium and has two main sub-types,transthyretin cardiac amyloidosis(ATTR)and immunoglobulin light chain cardiac amyloidosis(AL).ATTR is further dif-ferentiated into wild-type(wtATTR)and hereditary(hATTR),depending on the absence or presence of mutation in the trans-thyretin gene.The increased recognition of disease with the improvement in diagnostic armamentarium and serendipitous ad-vancements in the therapeutic landscape have changed the status of CA from being a rare and untreatable disease to being a not-so-rare and treatable disease.Both ATTR and AL have certain clinical aspects that can provide early clues for the disease.While electrocardiography followed by echocardiography and subsequently cardiac magnetic resonance can raise suspicion for CA,the definitive diagnosis of ATTR is non-invasively established by bone scintigraphy while that of AL always needs histological con-firmation.Severity of CA can be gauged by serum biomarker-based staging of both ATTR and AL.ATTR therapies work by silen-cing or stabilizing TTR or by degrading amyloid fibrils,while AL is managed with anti-plasma cell therapies and autologous stem cell transplant.
文摘Protein misfolding and aggregation into amyloid fibrils is the main pathological hallmark of neurodegenerative diseases,including Alzheimer’s,Parkinson’s,Huntington’s,and prion diseases(Chiti and Dobson,2017).These insoluble fibrillar deposits possess a common structure characterized by a cross-β-sheet conformation in which β-strands run transversely to the fiber axis and form an intermolecular network of hydrogen bonds.
基金supported by the National High Technology Research and Development Program of China("863"Program),No.2012AA020905the National Natural Science Foundation of China,No.81171143 and30971011+1 种基金National Natural Science Foundation of China(NSFC)/Research Grants Council(RGC) Joint Research Scheme,No.81161160570TsinghuaYue-Yuen Medical Sciences Fund
文摘Amyloid β-peptide,a major component of senile plaques in Alzheimer’s disease,has been implicated in neuronal cell death and cognitive impairment.Recently,studies have shown that the pathogenesis of cerebral ischemia is closely linked with Alzheimer’s disease.In this study,a rat model of global cerebral ischemia-reperfusion injury was established via occlusion of four arteries;meanwhile,fibrillar amyloidβ-peptide was injected into the rat lateral ventricle.The Morris water maze test and histological staining revealed that administration of amyloidβ-peptide could further aggravate impairments to learning and memory and neuronal cell death in the hippocampus of rats subjected to cerebral ischemia-reperfusion injury.Western blot showed that phosphorylation of tau protein and the activity of glycogen synthase kinase 3βwere significantly stronger in cerebral ischemia-reperfusion injury rats subjected to amyloid β-peptide administration than those undergoing cerebral ischemia-reperfusion or amyloidβ-peptide administration alone.Conversely,the activity of protein phosphatase 2A was remarkably reduced in rats with cerebral ischemia-reperfusion injury following amyloidβ-peptide administration.These findings suggest that amyloidβ-peptide can potentiate tau phosphorylation induced by cerebral ischemia-reperfusion and thereby aggravate cognitive impairment.
基金supported by grants from the Alzheimer’s Association (AARGD-18-566576)NIH/ NIA (RF1AG072491)NIH/NIAID (R01AI132695) to RM
文摘Potential causes for the clinical and pathological variability observed in Alzheimer’s disease(AD):AD is an age-related neurodegenerative disorder characterized by the impairment of cognitive functions such as memory,learning,and reasoning.These commonly described clinical symptoms are due to particular pathological changes in the brain,including inflammation,synaptic loss,and neuronal death.These changes are a consequence of the accumulation of abnormally folded amyloid-β(Aβ)and tau proteins in specific areas of the central nervous system.Considering the progressive aging of the world’s population,the number of people affected by AD is expected to substantially and consistently increase in the coming years.This positions AD as one of the main public health challenges in the near future.
基金financial support from the National Natural Science Foundation of China(22274102 and 22001182)the Sichuan Science and Technology Program(2022ZYD0027)+1 种基金the Open Research Fund of School of Chemistry and Chemical Engineering,Henan Normal University(2022A02)the Fundamental Research Funds for the Central Universities。
文摘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.
基金supported by the National Natural Science Foundation of China(No.22073088,No.22027801 and No.21873089).
文摘Nickel,an important transi-tion metal element,is one of the trace elements for hu-man body and has a crucial impact on life and health.Some evidences show the excess exposure to metal ions might be associated with neurological diseases.Herein,we applied Raman spectroscopy to study the Ni(II)ion effect on kinetics of amyloid fibrillation of hen egg white lysozyme(HEWL)in thermal and acidic conditions.Using the well-known Raman indicators for protein tertiary and secondary structures,we monitored and analyzed the concentration effect of Ni(II)ions on the unfolding of tertiary structures and the transformation of sec-ondary structures.The experimental evidence validates the accelerator role of the metal ion in the kinetics.Notably,the additional analysis of the amide I band profile,combined with thioflavin-T fluorescence assays,clearly indicates the inhibitory effect of Ni(II)ions on the formation of amyloid fibrils with organizedβ-sheets structures.Instead,a more significant promotion influence is affirmed on the assembly into other aggregates with disordered struc-tures.The present results provide rich information about the specific metal-mediated protein fibrillation.
基金The study was approved by the Biomedical Research Ethics Committee of West China Hospital,Sichuan University(2014No.37).
文摘BACKGROUND Islet amyloid deposition and reducedβ-cell mass are pathological hallmarks in type 2 diabetes mellitus subjects.To date,the pathological features of the islets in diabetes secondary to pancreatic ductal adenocarcinoma(PDAC)have not been specifically addressed.AIM To provide further insight into the relationship between islet amyloid deposition of the residual pancreas in PDAC patients and to explore whether regional differences(proximal vs distal residual pancreas)are associated with islet amyloid deposition.METHODS We retrospectively collected clinical information and pancreatic tissue removed from tumors of 45 PDAC patients,including 14 patients with normal glucose tolerance(NGT),16 patients with prediabetes and 15 new-onset diabetes(NOD)patients diagnosed before surgery by an oral glucose tolerance test at West China Hospital from July 2017 to June 2020.Pancreatic volume was calculated by multiplying the estimated area of pancreatic tissue on each image slice by the interval between slices based on abdominal computer tomography scans.Several sections of paraffin-embedded pancreas specimens from both the proximal and/or distal regions remote from the tumor were stained as follows:(1)Hematoxylin and eosin for general histological appearance;(2)hematoxylin and insulin for the determination of fractionalβ-cell area(immunohistochemistry);and(3)quadruple insulin,glucagon,thioflavin T and DAPI staining for the determination ofβ-cell area,α-cell area and amyloid deposits.RESULTS Screening for pancreatic histologic features revealed that duct obstruction with islet amyloid deposition,fibrosis and marked acinar atrophy were robust in the distal pancreatic regions but much less robust in the proximal regions,especially in the prediabetes and NOD groups.Consistent with this finding,the remnant pancreatic volume was markedly decreased in the NOD group by nearly one-half compared with that in the NGT group(37.35±12.16 cm^(3) vs 69.79±18.17 cm^(3),P<0.001).As expected,islets that stained positive for amyloid(islet amyloid density)were found in the majority of PDAC cases.The proportion of amyloid/islet area(severity of amyloid deposition)was significantly higher in both prediabetes and NOD patients than in NGT patients(P=0.002;P<0.0001,respectively).We further examined the regional differences in islet amyloid deposits.Islet amyloid deposit density was robustly increased by approximately 8-fold in the distal regions compared with that in the proximal regions in the prediabetes and NOD groups(3.98%±3.39%vs 0.50%±0.72%,P=0.01;12.03%vs 1.51%,P=0.001,respectively).CONCLUSION In conclusion,these findings suggest that robust alterations of the distal pancreas due to tumors can disturb islet function and structure with islet amyloid formation,which may be associated with the pathogenesis of NOD secondary to PDAC.
