Amyloid-β(Aβ)and tau,the two hallmark proteins associated with Alzheimer’s disease(AD),exhibit distinct toxic effects but also interact synergistically within the disease pathology.The prevailing theory in AD patho...Amyloid-β(Aβ)and tau,the two hallmark proteins associated with Alzheimer’s disease(AD),exhibit distinct toxic effects but also interact synergistically within the disease pathology.The prevailing theory in AD pathology-the amyloid cascade hypothesis-highlights the pivotal role of increased processing of the amyloid precursor protein(APP).Initially cleaved by the majorβ-secretase(β-amyloid cleaving enzyme-1,BACE1)in the brain,then undergoes further cleavage by theγ-secretase complex,resulting in the production of Aβ_(40-42)and a set of intracellular C-terminal peptides known as Aβand APP intracellular domain(β-AICDs)and soluble amyloid precursor proteinβ(sAPPβ)(Orobets and Karamyshev,2023).展开更多
Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticula...Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticularly,this hypothesis posits that in Alzheimer's disease,the aggregation of amyloid-beta peptide initiates a series of pathological processes leading to neuronal dysfunction and death(Zhang et al.,2024).展开更多
Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the...Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.展开更多
In the words of the late Sir Colin Blakemore,neurologists have historically sought to infer brain functions in a manner akin to to king a hammer to a computeranalyzing localized anatomical lesions caused by trauma,tum...In the words of the late Sir Colin Blakemore,neurologists have historically sought to infer brain functions in a manner akin to to king a hammer to a computeranalyzing localized anatomical lesions caused by trauma,tumors,or strokes,noting deficits,and inferring what functions certain brain regions may be responsible for.This approach exemplifies a deletion heuristic,where the absence of a specific function reveals insights about the underlying structures or mechanisms responsible for it.By observing what is lost when a particular brain region is damaged,throughout the history of the field,neurologists have pieced together the intricate relationship between anatomy and function.展开更多
Cardiac amyloidosis(CA)is characterized by the deposition of the misfolded amyloid precursor proteins in the myocardium of the heart.The systemic form of CA is mainly caused by either the misfolded monoclonal immunogl...Cardiac amyloidosis(CA)is characterized by the deposition of the misfolded amyloid precursor proteins in the myocardium of the heart.The systemic form of CA is mainly caused by either the misfolded monoclonal immunoglobulin light chains(kappa and lambda)or transthyretin.[1]The clinical manifestations are mainly overlap with symptoms of other cardiovascular diseases mostly hypertrophic cardiomyopathy and heart failure.Some cases often overlooked and remains undiagnosed because of the atypical clinical manifestations,especially in the elderly.展开更多
Objective To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A(SV2A)influences the distribution of amyloid precursor protein(APP)in the trans-Golgi network(TGN),endolysosomal system...Objective To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A(SV2A)influences the distribution of amyloid precursor protein(APP)in the trans-Golgi network(TGN),endolysosomal system,and cell membranes and to reveal the effects of SV2A on APP amyloid degradation.Methods Colocalization analysis of APP with specific tagged proteins in the TGN,ensolysosomal system,and cell membrane was performed to explore the effects of SV2A on the intracellular transport of APP.APP,β-site amyloid precursor protein cleaving enzyme 1(BACE1)expressions,and APP cleavage products levels were investigated to observe the effects of SV2A on APP amyloidogenic processing.Results APP localization was reduced in the TGN,early endosomes,late endosomes,and lysosomes,whereas it was increased in the recycling endosomes and cell membrane of SV2A-overexpressed neurons.Moreover,Arl5b(ADP-ribosylation factor 5b),a protein responsible for transporting APP from the TGN to early endosomes,was upregulated by SV2A.SV2A overexpression also decreased APP transport from the cell membrane to early endosomes by downregulating APP endocytosis.In addition,products of APP amyloid degradation,including sAPPβ,Aβ1-42,and Aβ1-40,were decreased in SV2A-overexpressed cells.Conclusion These results demonstrated that SV2A promotes APP transport from the TGN to early endosomes by upregulating Arl5b and promoting APP transport from early endosomes to recycling endosomes-cell membrane pathway,which slows APP amyloid degradation.展开更多
Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link b...Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.展开更多
The deposition of amyloid-beta is a pathological hallmark of Alzheimer＇s disease, Amyloid-beta is derived from amyloid precursor protein through sequential proteolytic cleavages by β-secretase （beta-site amyloid pr...The deposition of amyloid-beta is a pathological hallmark of Alzheimer＇s disease, Amyloid-beta is derived from amyloid precursor protein through sequential proteolytic cleavages by β-secretase （beta-site amyloid precursor protein-cleaving enzyme 1） and r-secretase. To further elucidate the roles of beta-site amyloid precursor protein-cleaving enzyme 1 in the development of AIzheimer＇s disease, a yeast two-hybrid system was used to screen a human embryonic brain cDNA library for proteins directly interacting with the intracellular domain of beta-site amyloid precursor protein-cleaving enzyme 1. A potential beta-site amyloid precursor protein-cleaving enzyme 1- interacting protein identified from the positive clones was divalent cation tolerance protein. Immunoprecipitation studies in the neuroblastoma cell line N2a showed that exogenous divalent cation tolerance protein interacts with endogenous beta-site amyloid precursor protein-cleaving enzyme 1. The overexpression of divalent cation tolerance protein did not affect beta-site amyloid precursor protein-cleaving enzyme 1 protein levels, but led to increased amyloid precursor protein levels in N2a/APP695 cells, with a concomitant reduction in the processing product amyloid precursor protein C-terminal fragment, indicating that divalent cation tolerance protein inhibits the processing of amyloid precursor protein. Our experimental findings suggest that divalent cation tolerance protein negatively regulates the function of beta-site amyloid precursor protein-cleaving enzyme 1. Thus, divalent cation tolerance protein could play a protective role in Alzheimer＇s disease.展开更多
Alzheimer's disease(AD)is a neurodegenerative disease characterized by a progressive decline in cognitive functions.Given that AD undermines the quality of life for millions and has an extended asymptomatic period...Alzheimer's disease(AD)is a neurodegenerative disease characterized by a progressive decline in cognitive functions.Given that AD undermines the quality of life for millions and has an extended asymptomatic period,exploring the full AD pathogenesis and seeking the optimal therapeutic solution have become critical and imperative.This allows researchers to intervene,delay,and potentially prevent AD progression.Several clinical imaging methods are utilized routinely to diagnose and monitor AD,such as magnetic resonance imaging(MRI),functional magnetic resonance imaging(fMRI),positron emission tomography(PET),and single photon emission computed tomography(SPECT).Nevertheless,due to their intrinsic drawbacks and restrictions,such as radiation concerns,high cost,long acquisition time,and low spatial resolution,their applications in AD research are limited,especially at the cellular and molecular levels.In contrast,optical microscopic imaging methods overcome these limitations,offering researchers a variety of approaches with distinct advantages to explore AD pathology on diverse models.In this review,we provide a comprehensive overview of commonly utilized optical microscopic imaging techniques in AD research and introduce their contributions to image amyloid beta(Aβ)species.These techniques include fluorescence microscopy(FM),confocal microscopy(CM),two-photon fluorescence microscopy(TPFM),super-resolution microscopy(SRM),expansion microscopy(ExM),and light-sheet fluorescence microscopy(LSFM).In addition,we introduce some related topics,such as the development of near-infrared(NIR)Aβprobes,the Aβplaque hypothesis,and Aβoligomer hypothesis,and the roles of microglia and astrocytes in AD progression.We believe optical microscopic imaging methods continue to play an indispensable role in deciphering the full pathogenesis of AD and advancing therapeutic strategies.展开更多
Compelling evidence demonstrates that the levels of peripheral amyloid-β(Aβ)fluctuate in Alzheimer’s disease(AD)patients.Moreover,Aβdeposits have been identified in peripheral tissues.However,the relevance of peri...Compelling evidence demonstrates that the levels of peripheral amyloid-β(Aβ)fluctuate in Alzheimer’s disease(AD)patients.Moreover,Aβdeposits have been identified in peripheral tissues.However,the relevance of peripheral Aβ(misfolded or not)in pathological situations,and the temporal appearance of these pathological fluctuations,are not well understood.The presence of misfolded Aβin peripheral compartments raises concerns on potential inter-individual transmissions considering the well-reported prion-like properties of this disease-associated protein.The latter is supported by multiple reports demonstrating that Aβmisfolding can be transmitted between humans and experimental animals through multiple routes of exposure.In this mini-review,we discuss the potential implications of peripheral,disease-associated Aβin disease mechanisms,as well as in diagnostic and therapeutic approaches.展开更多
Pathological and clinical variability in Alzheimer's disease(AD):AD is clinically cha racterized by progressive memory loss and cognitive impairment.From a pathological point of view,the main features of AD are th...Pathological and clinical variability in Alzheimer's disease(AD):AD is clinically cha racterized by progressive memory loss and cognitive impairment.From a pathological point of view,the main features of AD are the deposition of amyloid plaques(composed of amyloid-beta,Aβ)and neurofibrillary tangles containing hyperphosphorylated Tau in the brain,accompanied by neu ronal and synaptic loss,neuroinflammation and brain atrophy(Jellinger,2022).Regardless of these common traits,growing evidence shows increased heterogen eity in the brain of AD patients considering both clinical manifestations and pathological features.展开更多
In the article titled“Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease”published on pages 2467-2479,Issue 11,Volum...In the article titled“Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease”published on pages 2467-2479,Issue 11,Volume 19 of Neural Regeneration Research(Tang et al.,2024),there are some errors in selecting the appropriate images in Figure 7 by authors during assembling the images.展开更多
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 prote...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).展开更多
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 cau...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).展开更多
Amyloid fibrils are highly organized protein or peptide aggregates,often characterized by a distinctive supramolecular cross-β-sheet structure.The formation and accumulation of these structures have been traditionall...Amyloid fibrils are highly organized protein or peptide aggregates,often characterized by a distinctive supramolecular cross-β-sheet structure.The formation and accumulation of these structures have been traditionally associated with neural or systemic human diseases,such as Alzheimer’s disease,Parkinson’s disease,type-2 diabetes,or amyotrophic lateral sclerosis(Wei et al.,2017;Wittung-Stafshede,2023).展开更多
Autophagy directly regulates the amyloid beta-peptide(Aβ)clearance,and its dysfunction occurs in the early pathogenesis of Alzheimer's disease(AD).We previously reported that docosahexaenoic acid-acylated astaxan...Autophagy directly regulates the amyloid beta-peptide(Aβ)clearance,and its dysfunction occurs in the early pathogenesis of Alzheimer's disease(AD).We previously reported that docosahexaenoic acid-acylated astaxanthin monoester(AST-DHA)showed neuroprotection against AD pathology.However,its in-depth mechanism and autophagic responses in AD brains are poorly understood.Herein,SH-SY5Y cells overexpressing the Swedish mutation(K595N/M596L)of APP gene were established to preliminarily evaluate the actions of AST-DHA on reducing Aβ_(1-42)levels and regulating autophagy.In microglial BV2 cells,AST-DHA and free astaxanthin(F-AST)recovered p62 and LC3Ⅱ/Ⅰlevels,and restored autophagy flux by rescuing the late phase of microglial autophagy.Notably,autophagic inhibitor bafilomycin A1 blunted the abilities of AST-DHA to reduce Aβ_(1-42)and fibral Aβ,suggesting that AST-DHA probably promoted Aβclearance in a microglial autophagy-dependent manner.Further studies in APP/PS1 mice verified that dietary AST-DHA and F-AST promoted Aβphagocytosis via microglial autophagy.Significant decreases of Iba1 and p62 were observed around Aβplaque in the hippocampus and cortex using triple fluorescence staining.Furthermore,AST-DHA exhibited superior performance over F-AST in restoring autophagic dysfunction,ameliorating Aβburden and cognitive deficit.Our findings suggest a possible mechanism of AST-DHA in improving AD by which it restores microglial autophagy to facilitate cerebral Aβclearance.It supports the future application of AST-DHA as an autophagic regulator in maintaining brain function.展开更多
Background The diagnostic delay of cardiac amyloidosis(CA)is known to be substantially long.A prolonged time from symptoms onset to diagnosis negatively impacts quality of life and life expectancy of the affected pati...Background The diagnostic delay of cardiac amyloidosis(CA)is known to be substantially long.A prolonged time from symptoms onset to diagnosis negatively impacts quality of life and life expectancy of the affected patients.We aim to describe the role of the incidental finding of amyloid deposits in prostatic tissue as an early marker of CA.Methods A systematic cardiological evaluation,comprising ECG,echocardiogram and 99mTc-DPD scintigraphy,was offered to a cohort of 19 patients with incidental prostatic amyloidosis(PA)findings,propectively detected between 2014-2023,to assess cardiac involvement.Results The median age of the patients was 80.2 years(IQR:74.9-82.6 years).Histopathological study revealed amyloid deposits within the walls of small vessels(predominantly small arteries)in 18 patients and mainly in the stroma in the remaining case.All of them were immunohistochemically positive for transthyretin(ATTR)except one patient,with known myeloma,which was unconclusive fo ATTR.Clonal dyscrasia was excluded in the rest of the patients.Thirteen patients(68.4%)underwent all cardiological tests,4 patients(21.1%)underwent only ECG and echocardiographic evaluation and two patients(10.5%)refused to undergo any cardiological study.Among 13 individuals undergoing the complete evaluation,six patients were eventually diagnosed with CA(46.15%).All of them were asymptomatic from a cardiovascular point of view at the time of the prostate biopsy.Conclusion The finding of PA should prompt a complete cardiovascular examination,given the significant percentage of patients eventually diagnosed with early-stage CA.Multidisciplinary collaboration among different medical specialists must be encouraged,given the potential clinical impact of CA early diagnosis.展开更多
Amyloid-like proteins are critical for interfacial adhesion across various marine organisms and bacteria.However,the specific contributions of different functional residues remain unclear.Herein,we introduce an approa...Amyloid-like proteins are critical for interfacial adhesion across various marine organisms and bacteria.However,the specific contributions of different functional residues remain unclear.Herein,we introduce an approach to deconstruct and mimic these residues using synthetic homopolymers and random copolymers with phenyl,amino,carboxyl,and hydroxyl functional groups using reversible addition-fragmentation chain transfer(RAFT)polymerization.The resulting polymers,designed with comparable molecular weights(M_(n):10–20 kDa)and narrow dispersities(PDI<1.3),mimic the diverse surface chemistry of amyloid-like proteins,enabling systematic investigation of their adhesive properties.The interfacial adhesion forces of different polymer films were quantified using atomic force microscopy(AFM)with a colloidal probe.Remarkably copolymers with multiple functional groups demonstrated significantly enhanced adhesion compared to homopolymers,a trend corroborated by macroscopic shear strength and stability tests.These results highlight that the synergistic effects of multiple functional groups are crucial for achieving universal interfacial adhesion of macromolecules,offering insights into protein adhesion mechanisms,and guiding polymer-based interfacial modifications.展开更多
Dear Editor,We present a case of vitreous amyloidosis in a patient who was previously confirmed as familial amyloidosis polyneuropathy(FAP)because of peripheral neuropathy symptom onset.Even though the patient had alr...Dear Editor,We present a case of vitreous amyloidosis in a patient who was previously confirmed as familial amyloidosis polyneuropathy(FAP)because of peripheral neuropathy symptom onset.Even though the patient had already undergone liver transplantation 5y prior,the extracellular deposition of amyloid in vitreous body greatly infected the patient’s visual function.展开更多
BACKGROUND Alzheimer’s disease(AD)is a progressive neurodegenerative disorder currently lacking effective therapeutic interventions.Pathological hallmarks of AD include intracellular neurofibrillary tangles(NFTs)and ...BACKGROUND Alzheimer’s disease(AD)is a progressive neurodegenerative disorder currently lacking effective therapeutic interventions.Pathological hallmarks of AD include intracellular neurofibrillary tangles(NFTs)and extracellular amyloid beta(Aβ)plaques.Neuroplastin 65(NP65),highly expressed in the brain,has been previously shown to mitigate cognitive impairments and decrease Aβplaques in the AD mouse model,suggesting that NP65 is involved in AD neuropathology.However,direct evidence linking NP65 expression to AD pathogenesis in human brain remains absent.AIM To quantify NP65 isoform expression gradients across distinct neuroanatomical regions in the healthy brain and investigate the alterations of NP65 expression in the AD brain.METHODS Immunohistochemical,immunofluorescent and western blot analyses were used to investigate NP65 expression in 19 postmortem brains(AD=10,controls=9).Double immunostaining with 6E10 and or phosphorylated-microtubule-associated protein tau(AT-8,a marker for NFT)markers was performed to assess NP65 colocalization with Aβplaques and NFTs.RESULTS In controls,NP65 was highly expressed in a wide-range of brain areas.AD cases showed significantly increased NP65 immunoreactivity across multiple brain regions,including the frontal and temporal cortex,hippocampus,and cerebellum,compared to controls.Western blot analysis consistently confirmed significantly elevated NP65 expression in the hippocampus of AD patients relative to controls.Double immunostaining demonstrated partial colocalization of NP65 with NFTs and Aβplaques in AD brain tissue.CONCLUSION Our findings demonstrate a significant increase of NP65 protein,which colocalizes with NFTs and Aβplaques in AD brains,providing direct evidence supporting a critical role of NP65 expression in the neuropathological mechanisms of this disease.展开更多
文摘Amyloid-β(Aβ)and tau,the two hallmark proteins associated with Alzheimer’s disease(AD),exhibit distinct toxic effects but also interact synergistically within the disease pathology.The prevailing theory in AD pathology-the amyloid cascade hypothesis-highlights the pivotal role of increased processing of the amyloid precursor protein(APP).Initially cleaved by the majorβ-secretase(β-amyloid cleaving enzyme-1,BACE1)in the brain,then undergoes further cleavage by theγ-secretase complex,resulting in the production of Aβ_(40-42)and a set of intracellular C-terminal peptides known as Aβand APP intracellular domain(β-AICDs)and soluble amyloid precursor proteinβ(sAPPβ)(Orobets and Karamyshev,2023).
基金funded by the Russian Science Foundation(grant No.23-74-10092)(to AIS)。
文摘Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticularly,this hypothesis posits that in Alzheimer's disease,the aggregation of amyloid-beta peptide initiates a series of pathological processes leading to neuronal dysfunction and death(Zhang et al.,2024).
基金supported by the Nature Science Foundation of Liaoning Province,Nos.2022-MS-211,2021-MS-064,and 2024-MS-048(all to YC).
文摘Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.
文摘In the words of the late Sir Colin Blakemore,neurologists have historically sought to infer brain functions in a manner akin to to king a hammer to a computeranalyzing localized anatomical lesions caused by trauma,tumors,or strokes,noting deficits,and inferring what functions certain brain regions may be responsible for.This approach exemplifies a deletion heuristic,where the absence of a specific function reveals insights about the underlying structures or mechanisms responsible for it.By observing what is lost when a particular brain region is damaged,throughout the history of the field,neurologists have pieced together the intricate relationship between anatomy and function.
基金supported by the National Clinical Research Center for Geriatric Diseases Foundation of Chinese PLA General Hospital(NCRCG-PLAGH-2024007).
文摘Cardiac amyloidosis(CA)is characterized by the deposition of the misfolded amyloid precursor proteins in the myocardium of the heart.The systemic form of CA is mainly caused by either the misfolded monoclonal immunoglobulin light chains(kappa and lambda)or transthyretin.[1]The clinical manifestations are mainly overlap with symptoms of other cardiovascular diseases mostly hypertrophic cardiomyopathy and heart failure.Some cases often overlooked and remains undiagnosed because of the atypical clinical manifestations,especially in the elderly.
基金supported by grants from the State Key Program of the National Natural Science Foundation of China(grant number 82030064)Beijing Hospital Authority Youth Program(grant number QML20230812)+2 种基金Research and Development Foundation of Capital Medical University(grant number PYZ23052)National Natural Science Youth Cultivation Project of Xuanwu Hospital,Capital Medical University(grant number QNPY202317)Capital Medical University Research and Cultivation Fund(grant number PYZ23049).
文摘Objective To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A(SV2A)influences the distribution of amyloid precursor protein(APP)in the trans-Golgi network(TGN),endolysosomal system,and cell membranes and to reveal the effects of SV2A on APP amyloid degradation.Methods Colocalization analysis of APP with specific tagged proteins in the TGN,ensolysosomal system,and cell membrane was performed to explore the effects of SV2A on the intracellular transport of APP.APP,β-site amyloid precursor protein cleaving enzyme 1(BACE1)expressions,and APP cleavage products levels were investigated to observe the effects of SV2A on APP amyloidogenic processing.Results APP localization was reduced in the TGN,early endosomes,late endosomes,and lysosomes,whereas it was increased in the recycling endosomes and cell membrane of SV2A-overexpressed neurons.Moreover,Arl5b(ADP-ribosylation factor 5b),a protein responsible for transporting APP from the TGN to early endosomes,was upregulated by SV2A.SV2A overexpression also decreased APP transport from the cell membrane to early endosomes by downregulating APP endocytosis.In addition,products of APP amyloid degradation,including sAPPβ,Aβ1-42,and Aβ1-40,were decreased in SV2A-overexpressed cells.Conclusion These results demonstrated that SV2A promotes APP transport from the TGN to early endosomes by upregulating Arl5b and promoting APP transport from early endosomes to recycling endosomes-cell membrane pathway,which slows APP amyloid degradation.
文摘Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.
基金supported by the National Natural Science Foundation of China, No. 81171192XMU Basic Training Program of Undergraduate, No. CXB2011019Visiting Scholar Fellowship of Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering of Xiamen University, No. 201101
文摘The deposition of amyloid-beta is a pathological hallmark of Alzheimer＇s disease, Amyloid-beta is derived from amyloid precursor protein through sequential proteolytic cleavages by β-secretase （beta-site amyloid precursor protein-cleaving enzyme 1） and r-secretase. To further elucidate the roles of beta-site amyloid precursor protein-cleaving enzyme 1 in the development of AIzheimer＇s disease, a yeast two-hybrid system was used to screen a human embryonic brain cDNA library for proteins directly interacting with the intracellular domain of beta-site amyloid precursor protein-cleaving enzyme 1. A potential beta-site amyloid precursor protein-cleaving enzyme 1- interacting protein identified from the positive clones was divalent cation tolerance protein. Immunoprecipitation studies in the neuroblastoma cell line N2a showed that exogenous divalent cation tolerance protein interacts with endogenous beta-site amyloid precursor protein-cleaving enzyme 1. The overexpression of divalent cation tolerance protein did not affect beta-site amyloid precursor protein-cleaving enzyme 1 protein levels, but led to increased amyloid precursor protein levels in N2a/APP695 cells, with a concomitant reduction in the processing product amyloid precursor protein C-terminal fragment, indicating that divalent cation tolerance protein inhibits the processing of amyloid precursor protein. Our experimental findings suggest that divalent cation tolerance protein negatively regulates the function of beta-site amyloid precursor protein-cleaving enzyme 1. Thus, divalent cation tolerance protein could play a protective role in Alzheimer＇s disease.
基金supported by NIH(R01AG055413),(R01AG085562),(R21AG059134),(R21AG078749),and(S10OD028609)awards(C.R.).NIH Office of the Director,National Institute on Aging.
文摘Alzheimer's disease(AD)is a neurodegenerative disease characterized by a progressive decline in cognitive functions.Given that AD undermines the quality of life for millions and has an extended asymptomatic period,exploring the full AD pathogenesis and seeking the optimal therapeutic solution have become critical and imperative.This allows researchers to intervene,delay,and potentially prevent AD progression.Several clinical imaging methods are utilized routinely to diagnose and monitor AD,such as magnetic resonance imaging(MRI),functional magnetic resonance imaging(fMRI),positron emission tomography(PET),and single photon emission computed tomography(SPECT).Nevertheless,due to their intrinsic drawbacks and restrictions,such as radiation concerns,high cost,long acquisition time,and low spatial resolution,their applications in AD research are limited,especially at the cellular and molecular levels.In contrast,optical microscopic imaging methods overcome these limitations,offering researchers a variety of approaches with distinct advantages to explore AD pathology on diverse models.In this review,we provide a comprehensive overview of commonly utilized optical microscopic imaging techniques in AD research and introduce their contributions to image amyloid beta(Aβ)species.These techniques include fluorescence microscopy(FM),confocal microscopy(CM),two-photon fluorescence microscopy(TPFM),super-resolution microscopy(SRM),expansion microscopy(ExM),and light-sheet fluorescence microscopy(LSFM).In addition,we introduce some related topics,such as the development of near-infrared(NIR)Aβprobes,the Aβplaque hypothesis,and Aβoligomer hypothesis,and the roles of microglia and astrocytes in AD progression.We believe optical microscopic imaging methods continue to play an indispensable role in deciphering the full pathogenesis of AD and advancing therapeutic strategies.
基金supported by grants from NIH(RF1AG072491 and R01AI132695)to RM.
文摘Compelling evidence demonstrates that the levels of peripheral amyloid-β(Aβ)fluctuate in Alzheimer’s disease(AD)patients.Moreover,Aβdeposits have been identified in peripheral tissues.However,the relevance of peripheral Aβ(misfolded or not)in pathological situations,and the temporal appearance of these pathological fluctuations,are not well understood.The presence of misfolded Aβin peripheral compartments raises concerns on potential inter-individual transmissions considering the well-reported prion-like properties of this disease-associated protein.The latter is supported by multiple reports demonstrating that Aβmisfolding can be transmitted between humans and experimental animals through multiple routes of exposure.In this mini-review,we discuss the potential implications of peripheral,disease-associated Aβin disease mechanisms,as well as in diagnostic and therapeutic approaches.
基金supported by a grant from NIH(R01AI132695)to RM。
文摘Pathological and clinical variability in Alzheimer's disease(AD):AD is clinically cha racterized by progressive memory loss and cognitive impairment.From a pathological point of view,the main features of AD are the deposition of amyloid plaques(composed of amyloid-beta,Aβ)and neurofibrillary tangles containing hyperphosphorylated Tau in the brain,accompanied by neu ronal and synaptic loss,neuroinflammation and brain atrophy(Jellinger,2022).Regardless of these common traits,growing evidence shows increased heterogen eity in the brain of AD patients considering both clinical manifestations and pathological features.
文摘In the article titled“Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease”published on pages 2467-2479,Issue 11,Volume 19 of Neural Regeneration Research(Tang et al.,2024),there are some errors in selecting the appropriate images in Figure 7 by authors during assembling the images.
基金funded by the Spanish Ministry of Science and Innovation(PDC2021-120914-I00)the Universitat Autònoma de Barcelona(PROOF OF CONCEPT 2020)ICREA,ICREA-Academia 2015 and 2020(to SV).
文摘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).
基金supported by grants PID2020-115823-GB100 funded by MCIN/AEI/10.13039/501100011033SBPLY/21/180501/000150 funded by JCCM/ERDF-A way of making Europe+1 种基金2022-GRIN-34354 grant by UCLM/ERDF intramural funding to LJDJDNL.DJ held a predoctoral fellowship granted by UCLM/ESF“Plan Propio de Investigación.”。
文摘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).
文摘Amyloid fibrils are highly organized protein or peptide aggregates,often characterized by a distinctive supramolecular cross-β-sheet structure.The formation and accumulation of these structures have been traditionally associated with neural or systemic human diseases,such as Alzheimer’s disease,Parkinson’s disease,type-2 diabetes,or amyotrophic lateral sclerosis(Wei et al.,2017;Wittung-Stafshede,2023).
基金supported by the National Natural Science Foundation of China(32302063)Shandong Provincial Natural Science Foundation(ZR2023QC130)。
文摘Autophagy directly regulates the amyloid beta-peptide(Aβ)clearance,and its dysfunction occurs in the early pathogenesis of Alzheimer's disease(AD).We previously reported that docosahexaenoic acid-acylated astaxanthin monoester(AST-DHA)showed neuroprotection against AD pathology.However,its in-depth mechanism and autophagic responses in AD brains are poorly understood.Herein,SH-SY5Y cells overexpressing the Swedish mutation(K595N/M596L)of APP gene were established to preliminarily evaluate the actions of AST-DHA on reducing Aβ_(1-42)levels and regulating autophagy.In microglial BV2 cells,AST-DHA and free astaxanthin(F-AST)recovered p62 and LC3Ⅱ/Ⅰlevels,and restored autophagy flux by rescuing the late phase of microglial autophagy.Notably,autophagic inhibitor bafilomycin A1 blunted the abilities of AST-DHA to reduce Aβ_(1-42)and fibral Aβ,suggesting that AST-DHA probably promoted Aβclearance in a microglial autophagy-dependent manner.Further studies in APP/PS1 mice verified that dietary AST-DHA and F-AST promoted Aβphagocytosis via microglial autophagy.Significant decreases of Iba1 and p62 were observed around Aβplaque in the hippocampus and cortex using triple fluorescence staining.Furthermore,AST-DHA exhibited superior performance over F-AST in restoring autophagic dysfunction,ameliorating Aβburden and cognitive deficit.Our findings suggest a possible mechanism of AST-DHA in improving AD by which it restores microglial autophagy to facilitate cerebral Aβclearance.It supports the future application of AST-DHA as an autophagic regulator in maintaining brain function.
文摘Background The diagnostic delay of cardiac amyloidosis(CA)is known to be substantially long.A prolonged time from symptoms onset to diagnosis negatively impacts quality of life and life expectancy of the affected patients.We aim to describe the role of the incidental finding of amyloid deposits in prostatic tissue as an early marker of CA.Methods A systematic cardiological evaluation,comprising ECG,echocardiogram and 99mTc-DPD scintigraphy,was offered to a cohort of 19 patients with incidental prostatic amyloidosis(PA)findings,propectively detected between 2014-2023,to assess cardiac involvement.Results The median age of the patients was 80.2 years(IQR:74.9-82.6 years).Histopathological study revealed amyloid deposits within the walls of small vessels(predominantly small arteries)in 18 patients and mainly in the stroma in the remaining case.All of them were immunohistochemically positive for transthyretin(ATTR)except one patient,with known myeloma,which was unconclusive fo ATTR.Clonal dyscrasia was excluded in the rest of the patients.Thirteen patients(68.4%)underwent all cardiological tests,4 patients(21.1%)underwent only ECG and echocardiographic evaluation and two patients(10.5%)refused to undergo any cardiological study.Among 13 individuals undergoing the complete evaluation,six patients were eventually diagnosed with CA(46.15%).All of them were asymptomatic from a cardiovascular point of view at the time of the prostate biopsy.Conclusion The finding of PA should prompt a complete cardiovascular examination,given the significant percentage of patients eventually diagnosed with early-stage CA.Multidisciplinary collaboration among different medical specialists must be encouraged,given the potential clinical impact of CA early diagnosis.
基金supported by the National Natural Science Foundation of China(Nos.22375122 and 22105065)the National Science Fund for Distinguished Young Scholars(No.52225301)+3 种基金the National Key R&D Program of China(Nos.2020YFA0710400 and 2020YFA0710402)the 111 Project(No.B14041)Fundamental Research Funds for Central Universities(No.GK202304040)Open Project of the State Key Laboratory of Supramolecular Structure and Materials(No.sklssm2024023)。
文摘Amyloid-like proteins are critical for interfacial adhesion across various marine organisms and bacteria.However,the specific contributions of different functional residues remain unclear.Herein,we introduce an approach to deconstruct and mimic these residues using synthetic homopolymers and random copolymers with phenyl,amino,carboxyl,and hydroxyl functional groups using reversible addition-fragmentation chain transfer(RAFT)polymerization.The resulting polymers,designed with comparable molecular weights(M_(n):10–20 kDa)and narrow dispersities(PDI<1.3),mimic the diverse surface chemistry of amyloid-like proteins,enabling systematic investigation of their adhesive properties.The interfacial adhesion forces of different polymer films were quantified using atomic force microscopy(AFM)with a colloidal probe.Remarkably copolymers with multiple functional groups demonstrated significantly enhanced adhesion compared to homopolymers,a trend corroborated by macroscopic shear strength and stability tests.These results highlight that the synergistic effects of multiple functional groups are crucial for achieving universal interfacial adhesion of macromolecules,offering insights into protein adhesion mechanisms,and guiding polymer-based interfacial modifications.
文摘Dear Editor,We present a case of vitreous amyloidosis in a patient who was previously confirmed as familial amyloidosis polyneuropathy(FAP)because of peripheral neuropathy symptom onset.Even though the patient had already undergone liver transplantation 5y prior,the extracellular deposition of amyloid in vitreous body greatly infected the patient’s visual function.
基金the National Natural Science Foundation of China,No.81771441 and No.81371213the Natural Science Foundation of Shanghai,No.21ZR1468400.
文摘BACKGROUND Alzheimer’s disease(AD)is a progressive neurodegenerative disorder currently lacking effective therapeutic interventions.Pathological hallmarks of AD include intracellular neurofibrillary tangles(NFTs)and extracellular amyloid beta(Aβ)plaques.Neuroplastin 65(NP65),highly expressed in the brain,has been previously shown to mitigate cognitive impairments and decrease Aβplaques in the AD mouse model,suggesting that NP65 is involved in AD neuropathology.However,direct evidence linking NP65 expression to AD pathogenesis in human brain remains absent.AIM To quantify NP65 isoform expression gradients across distinct neuroanatomical regions in the healthy brain and investigate the alterations of NP65 expression in the AD brain.METHODS Immunohistochemical,immunofluorescent and western blot analyses were used to investigate NP65 expression in 19 postmortem brains(AD=10,controls=9).Double immunostaining with 6E10 and or phosphorylated-microtubule-associated protein tau(AT-8,a marker for NFT)markers was performed to assess NP65 colocalization with Aβplaques and NFTs.RESULTS In controls,NP65 was highly expressed in a wide-range of brain areas.AD cases showed significantly increased NP65 immunoreactivity across multiple brain regions,including the frontal and temporal cortex,hippocampus,and cerebellum,compared to controls.Western blot analysis consistently confirmed significantly elevated NP65 expression in the hippocampus of AD patients relative to controls.Double immunostaining demonstrated partial colocalization of NP65 with NFTs and Aβplaques in AD brain tissue.CONCLUSION Our findings demonstrate a significant increase of NP65 protein,which colocalizes with NFTs and Aβplaques in AD brains,providing direct evidence supporting a critical role of NP65 expression in the neuropathological mechanisms of this disease.
