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
Introduction: Amyloidosis are systemic conditions and carpal tunnel syndrome (CTS) precedes the principal systemic complications and can be used as an early marker. Our objective was to determine the frequency of amyl...Introduction: Amyloidosis are systemic conditions and carpal tunnel syndrome (CTS) precedes the principal systemic complications and can be used as an early marker. Our objective was to determine the frequency of amyloid deposition in idiopathic CTS and its systemic impact. Methods: We retrospectively evaluated patients with CTS between September 2019 to January 2020. Samples from the anterior carpal ligament were pathologically evaluated and amyloid deposition was confirmed by apple-green birefringence on polarized light using Congo red stain. When amyloid was detected we performed genetic testing for transthyretin variants (ATTRv), immunofixation electrophoresis in serum and urine for light chains and multidisciplinary evaluation. Results: Thirty consecutive patients were included, 19 women, 11 men, mean age 70 years old (range 42 - 89 years). We identified 3 patients (10%) with amyloid deposits (mean age: 78.6 years, 2 men, 1 woman). Genetic testing for ATTRv and light chains studies were negative. During follow-up: The first patient required aortic valve replacement. The second patient developed progressive cardiac failure with syncopal episodes, atrioventricular block and atrial fibrillation and required a pacemaker and anticoagulation. The third patient had unexplained chronic edemas. The cardiac evaluation in all 3 patients revealed left ventricular hypertrophy and myocardial uptake (Perugini Score > 2) in their nuclear bone scintigraphies with technetium pyrophosphate. Two patients were treated with tafamidis and one patient died due to refractory cardiac insufficiency. Discussion: Our findings underline the importance of investigating amyloidosis in idiopathic CTS. The identification of deposits allows early diagnosis of cardiac amyloidosis leading to timely intervention and treatment.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
Need for Alzheimer's disease progression monitoring:Alzheimer's disease(AD)is an irreversible progressive brain disorder that causes severe and incurable neuro-impairment.The World Health Organization estimate...Need for Alzheimer's disease progression monitoring:Alzheimer's disease(AD)is an irreversible progressive brain disorder that causes severe and incurable neuro-impairment.The World Health Organization estimates that 55 million people are affected by AD dementia by 2020 which may exceed 78 million by 2030 and 139 in 2050.The estimated cost to manage AD is above US$1.3 trillion,which will further increase to US$2.8 trillion by 2030.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
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
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
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
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
BACKGROUND Necrotising enterocolitis(NEC)is a critical gastrointestinal emergency affecting premature and low-birth-weight neonates.Serum amyloid A(SAA),procalcitonin(PCT),and high-mobility group box 1(HMGB1)have emer...BACKGROUND Necrotising enterocolitis(NEC)is a critical gastrointestinal emergency affecting premature and low-birth-weight neonates.Serum amyloid A(SAA),procalcitonin(PCT),and high-mobility group box 1(HMGB1)have emerged as potential biomarkers for NEC due to their roles in inflammatory response,tissue damage,and immune regulation.AIM To evaluate the diagnostic value of SAA,PCT,and HMGB1 in the context of NEC in newborns.METHODS The study retrospectively analysed the clinical data of 48 newborns diagnosed with NEC and 50 healthy newborns admitted to the hospital.Clinical,radiological,and laboratory findings,including serum SAA,PCT,and HMGB1 Levels,were collected,and specific detection methods were used.The diagnostic value of the biomarkers was evaluated through statistical analysis,which was performed using chi-square test,t-test,correlation analysis,and receiver operating characteristic(ROC)analysis.RESULTS The study demonstrated significantly elevated levels of serum SAA,PCT,and HMGB1 Levels in newborns diagnosed with NEC compared with healthy controls.The correlation analysis indicated strong positive correlations among serum SAA,PCT,and HMGB1 Levels and the presence of NEC.ROC analysis revealed promising sensitivity and specificity for serum SAA,PCT,and HMGB1 Levels as potential diagnostic markers.The combined model of the three biomarkers demonstrating an extremely high area under the curve(0.908).CONCLUSION The diagnostic value of serum SAA,PCT,and HMGB1 Levels in NEC was highlighted.These biomarkers potentially improve the early detection,risk stratification,and clinical management of critical conditions.The findings suggest that these biomarkers may aid in timely intervention and the enhancement of outcomes for neonates affected by NEC.展开更多
The use of anticoagulation therapy could prove to be controversial when trying to balance ischemic stroke and intracranial bleeding risks in patients with concurrent cerebral amyloid angiopathy(CAA)and atrial fibrilla...The use of anticoagulation therapy could prove to be controversial when trying to balance ischemic stroke and intracranial bleeding risks in patients with concurrent cerebral amyloid angiopathy(CAA)and atrial fibrillation(AF).In fact,CAA is an age-related cerebral vasculopathy that predisposes patients to intracerebral hemorrhage.Nevertheless,many AF patients require oral systemic dose-adjusted warfarin,direct oral anticoagulants(such as factor Xa inhibitors)or direct thrombin inhibitors to control often associated with cardioembolic stroke risk.The prevalence of both CAA and AF is expected to rise,due to the aging of the population.This clinical dilemma is becoming increasingly common.In patients with coexisting AF and CAA,the risks/benefits profile of anticoagulant therapy must be assessed for each patient individually due to the lack of a clear-cut consensus with regard to its risks in scientific literature.This review aims to provide an overview of the management of patients with concomitant AF and CAA and proposes the implementation of a risk-based decision-making algorithm.展开更多
Increasing evidence demonstrated that the blood-brain barrier(BBB)was involved in developing cerebral amyloid angiopathy(CAA).The BBB participates in the neurovascular coupling and regulates the transport of substance...Increasing evidence demonstrated that the blood-brain barrier(BBB)was involved in developing cerebral amyloid angiopathy(CAA).The BBB participates in the neurovascular coupling and regulates the transport of substances,which is closely related to neurodegenerative diseases.In CAA,the deposition of amyloid beta(Aβ)in arteries,capillaries,and arterioles of meninges and cerebral cortex results in the destruction of the BBB,chronic inflammatory response,chronic cerebral hypoperfusion,and dysfunction of the neurovascular unit,which eventually leads to neurodegeneration.At the same time,CAA is an age-related disease.Patients with CAA often have some risk factors for cerebrovascular diseases,such as hypertension and diabetes,which can further aggravate the damage to the BBB.Thus,it is of great significance to pay attention to the BBB in the pathogenesis and future intervention targets of CAA.Therefore,this manuscript reviewed the dysfunction of the BBB in CAA.展开更多
Cerebral amyloid angiopathy(CAA)is a small vessel disease of the brain characterized by the progressive deposition of amyloid-β(Aβ)plaques in the walls of cerebral blood vessels.It presents with a subtle course and ...Cerebral amyloid angiopathy(CAA)is a small vessel disease of the brain characterized by the progressive deposition of amyloid-β(Aβ)plaques in the walls of cerebral blood vessels.It presents with a subtle course and sudden onset,and currently,there are no specific therapeutic interventions available.Accurate diagnosis of CAA could enable targeted interventions in the early stages of the disease,potentially mitigating the disease’s effects.Herein,we review the primary imaging biomarkers used in the diagnosis of CAA,including their mechanisms,imaging characteristics,and significance.We also provide an interpretation of the latest version(v2.0)of the Boston criteria,which are commonly used in the clinical diagnosis of CAA.Additionally,this study introduces various positron emission tomography(PET)tracers for CAA and reviews their application values in the diagnosis of CAA.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
Objective: To construct a PC12 cell strain with neuronal differentiation, and observe the apoptosis and pro- liferation activity effects induced these cells by Amyloid beta-Protein (Aβ-43). Methods: 1) PC12 cells in...Objective: To construct a PC12 cell strain with neuronal differentiation, and observe the apoptosis and pro- liferation activity effects induced these cells by Amyloid beta-Protein (Aβ-43). Methods: 1) PC12 cells in logarithmic growth phase were subcultured for 24 h. After the culture fluid was changed, the cells were treated with Rat-β-NGF and cultured for 9 days. 2) Neuronal differentiation of PC12 cells in logarithmic growth phase were divided into four groups: control group (0), experimental group (1), experimental group (2) and experimental group (3). The concentrations of Aβ in the four groups were 0 μmol/L, 1.25 μmol/L, 2.5 μmol/L and 5 μmol/L, respectively. The cells were harvested at 24, 48 and 72 h later and stained with AnnexinV-FITC/PI after centrifugation and washing. Then flow cytometry was conducted to examine the apoptosis percentage. 3) NGF-induced PC12 cells were selected and Aβ with different concentrations was added. The final concentrations of Aβ were 0 μmol/L, 1.25 μmol/L, 2.5 μmol/L and 5 μmol/L, respectively. After the cells were incubated in an atmosphere of 5% CO2 at 37 °C in an incubator for 72 h, the OD values were examined. Results: 1) Neuronal differentiated PC12 cell lines were successfully established. 2) Flow cytometric examination indicated that Aβ (1.25, 2.5, and 5.0 μmol/L) could effectively induce apoptosis of neuronal-differented cells at the 24 h, 48 h and 72 h time points. 3) Aβ (0?5.00 μmol/L) had no obvious effect on proliferation or restraining of the neuronal differentiation of the PC12 cells after a 72 h interacting process. Conclusion: This investigation revealed successful neuronal differentiation of the PC12 cell strain. The induction of apoptosis of the neurocytes by various concentrations of Aβ was observed and the in- fluence of Aβ on induced proliferation of PC12 cells by Rat-β-NGF was revealed. This study may provide basis for future research on the molecular cure of AD and interdiction of AD evolution.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
BACKGROUND： The findings about the alterations in cerebrospinal fluid beta-amyloid protein （Aβ ） and apolipoprotein E （APOE） after subarachnoid hemorrhage indicate that they have significant correlation with pro...BACKGROUND： The findings about the alterations in cerebrospinal fluid beta-amyloid protein （Aβ ） and apolipoprotein E （APOE） after subarachnoid hemorrhage indicate that they have significant correlation with prognosis of patients. OBJECTⅣE： To observe the alterations in cerebrospinal fluid Aβ and ApoE after subarachnoid hemorrhage （SAH）. DESIGN： Contrast observation. SETTING： Department of Neurosurgery, the First Hospital of Lanzhou University. PARTICIPANTS： A total of 25 SAH patients including 16 males and 9 females aged from 13 to 72 years were selected form Department of Neurosurgery, the First Affiliated Hospital of Lanzhou University from October 2003 to February 2004. The Hunt-Hess grade ranged from Ⅰ to Ⅳ, and patients admitted hospital in 24 hours after invasion, affirmed by the brain CT scan and lumbar vertebra puncture, no other severe complications and important organs＇ functional defect and severe infection, no hematological system disease. METHODS- All admitted patients were collected CSF by lumbar vertebra puncture in 24 hours. The cerebrospinal fluid （CSF） of control group came from the admitted 15 patients of our hospital that have no nervous system disease. Aβ content was detected by enzyme linked immunosorbent assay （ELISA）, the kit was provided by the Central Laboratory of the First Hospital of Lanzhou University; ApoE concentration was detected by monoclone enzyme linked immunosorbent assay （ELISA）, the kit was provided by the Immunotechnique Research Institute of the Fourth Military Medical University. S100B concentration was detected by enzyme linked immunosorbent assay double antibody sandwich method, the kit was provided by the Physiological Research Room of the Fourth Military Medical University. The data were indicated on Mean±SD and were analyzed by SPSS 10.0 statistical package. All data were handled through test of significance variance analysis, and groups were compared through independent sampler t test. The concentration was handled through Pearson correlation analysis between Aβ and ApoE. The relationship between Aβ, ApoE concentration with pathogenetic condition and prognosis of the patients was handled through Spearman ranking correlation analysis. MAIN OUTCOME MEASURES：① The concentration of ApoE, Aβ and S100B after SAH in contrast to the control group in CSF by different Hunt-Hess and Glasgow Outcome Scale （GOS） grades; ② The level of correlation between ApoE and Aβ ; ③Correlation between ApoE and Aβ in pathogenetic condition and prognosis of the patients. RESULTS： All 25 SAH patients and 15 controls were involved in the final analysis. ① The concentration of ApoE, Aβ and S100B in CSF： The concentration of ApoE decreased after SAH in contrast to the control group [（0.46±0.007）, （0.85±0.11） μg/L, P 〈 0.01], the concentration of ApoE decreased after SAH in contrast to the control group [（5.36± 1.19）, （8.41± 1.60） μg/L, P 〈 0.01], and the concentration of S100B increased after SAH in contrast to the control group [（18.60±7.31）, （6.56±1.02） pg/L, P 〈 0.01]. ② The concentration of ApoE, Aβ and S100B in CSF after SAH on different Hunt-Hess and GOS grades： The concentration of Aβ in Hunt-Hess Ⅰ -Ⅲ grade was higher than Hunt-Hess Ⅳ, Ⅴ grade [（6.63 ± 1.25）, （3.35± 1.02） μg/L, P 〈 0.01], and the concentration of ApoE in Hunt-Hess Ⅰ- Ⅲ grade was higher than Hunt-Hess Ⅳ, Ⅴ grade [（0.56±0.07）, （0.38±0.04） μg/L, P 〈 0.05], the concentration of S100B in Hunt-Hess Ⅰ - Ⅲ grade was lower than Hunt-Hess Ⅳ - Ⅴ grade [（16.32±5.58）, （22.85±8.10） pg/L, P 〈 0.01]; the concentration of Aβ in GOS Ⅰ - Ⅲ grade was lower than GOS Ⅳ, Ⅴ grade [（3.76± 1.04）, （5.89±1.20） μg/L, P 〈 0.01], and the concentration of ApoE in GOS Ⅰ - Ⅲ grade was lower than GOS Ⅳ, Ⅴ grade [（0.32±0.02）, （0.58±0.07） μg/L, P 〈 0.011, and the concentration of S100B in GOS Ⅰ - Ⅲ grade was higher than GOS Ⅳ, Ⅴ grade [（25.36±9.70）, （14.33±6.69） pg/L, P 〈 0.01].③ The results of Pearson correlation analysis and Spearman ranking correlation analysis： There was significantly positive correlation between CSF Aβ concentration and clinical outcome （r=0.65, P 〈 0.01）, and the decrease in CSF Aβ concentration correlated significant with that of ApoE （r =0.85, P 〈 0.01）. CONCLUSION： There is a significant decrease in both Aβ and ApoE in the CSF after SAH, and there is significant correlation between CSF Aβ and ApoE concentration with clinical outcome, the interactions between these proteins may have important effects on SAH, ApoE and Aβ as surrogate markers for the outcome of patients with SAH.展开更多
Aim: The abnormal accumulation, assembly and deposition of the amyloid β-protein (Aβ) are prominent pathological features of patients with Alzheimer’s disease (AD) and related disorders. A number of factors in the ...Aim: The abnormal accumulation, assembly and deposition of the amyloid β-protein (Aβ) are prominent pathological features of patients with Alzheimer’s disease (AD) and related disorders. A number of factors in the brain can influence Aβ accumulation and associated pathologies. The aim of the present study was to determine the consequences of deleting nitric oxide synthase (NOS) 3, the endothelial form of NOS, in Tg-5xFAD mice, a model of parenchymal AD-like amyloid pathology. Methods: Tg-5xFAD mice were bred with NOS3-/- mice. Cohorts of Tg-5xFAD mice and bigenic Tg-5xFAD/NOS3-/- mice were aged to six months followed by collection of the blood and brain tissues from the mice for biochemical and pathological analyses. Results: ELISA analyses show that the absence of NOS3 results in elevated levels of cerebral and plasma Aβ peptides in Tg-5xFAD mice. Immunohistochemical analyses show that the absence of NOS3 increased the amount of parenchymal Aβ deposition and fibrillar amyloid accumulation in Tg-5xFAD mice. The elevated levels of Aβ were not due to changes in the expression levels of transgene encoded human amyloid precursor protein (APP), endogenous β-secretase, or increased proteolytic processing of APP. Conclusions: The results from this study suggest that the loss of NOS3 activity enhances Aβ pathology in Tg-5xFAD mice. These findings are similar to previous studies of NOS2 deletion suggesting that reduced NOS activity and NO levels enhance amyloid-associated pathologies in human APP transgenic mice.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
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Introduction: Amyloidosis are systemic conditions and carpal tunnel syndrome (CTS) precedes the principal systemic complications and can be used as an early marker. Our objective was to determine the frequency of amyloid deposition in idiopathic CTS and its systemic impact. Methods: We retrospectively evaluated patients with CTS between September 2019 to January 2020. Samples from the anterior carpal ligament were pathologically evaluated and amyloid deposition was confirmed by apple-green birefringence on polarized light using Congo red stain. When amyloid was detected we performed genetic testing for transthyretin variants (ATTRv), immunofixation electrophoresis in serum and urine for light chains and multidisciplinary evaluation. Results: Thirty consecutive patients were included, 19 women, 11 men, mean age 70 years old (range 42 - 89 years). We identified 3 patients (10%) with amyloid deposits (mean age: 78.6 years, 2 men, 1 woman). Genetic testing for ATTRv and light chains studies were negative. During follow-up: The first patient required aortic valve replacement. The second patient developed progressive cardiac failure with syncopal episodes, atrioventricular block and atrial fibrillation and required a pacemaker and anticoagulation. The third patient had unexplained chronic edemas. The cardiac evaluation in all 3 patients revealed left ventricular hypertrophy and myocardial uptake (Perugini Score > 2) in their nuclear bone scintigraphies with technetium pyrophosphate. Two patients were treated with tafamidis and one patient died due to refractory cardiac insufficiency. Discussion: Our findings underline the importance of investigating amyloidosis in idiopathic CTS. The identification of deposits allows early diagnosis of cardiac amyloidosis leading to timely intervention and treatment.
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Florida Polytechnic University,Lakeland,USA for providing support。
文摘Need for Alzheimer's disease progression monitoring:Alzheimer's disease(AD)is an irreversible progressive brain disorder that causes severe and incurable neuro-impairment.The World Health Organization estimates that 55 million people are affected by AD dementia by 2020 which may exceed 78 million by 2030 and 139 in 2050.The estimated cost to manage AD is above US$1.3 trillion,which will further increase to US$2.8 trillion by 2030.
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).
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BACKGROUND Necrotising enterocolitis(NEC)is a critical gastrointestinal emergency affecting premature and low-birth-weight neonates.Serum amyloid A(SAA),procalcitonin(PCT),and high-mobility group box 1(HMGB1)have emerged as potential biomarkers for NEC due to their roles in inflammatory response,tissue damage,and immune regulation.AIM To evaluate the diagnostic value of SAA,PCT,and HMGB1 in the context of NEC in newborns.METHODS The study retrospectively analysed the clinical data of 48 newborns diagnosed with NEC and 50 healthy newborns admitted to the hospital.Clinical,radiological,and laboratory findings,including serum SAA,PCT,and HMGB1 Levels,were collected,and specific detection methods were used.The diagnostic value of the biomarkers was evaluated through statistical analysis,which was performed using chi-square test,t-test,correlation analysis,and receiver operating characteristic(ROC)analysis.RESULTS The study demonstrated significantly elevated levels of serum SAA,PCT,and HMGB1 Levels in newborns diagnosed with NEC compared with healthy controls.The correlation analysis indicated strong positive correlations among serum SAA,PCT,and HMGB1 Levels and the presence of NEC.ROC analysis revealed promising sensitivity and specificity for serum SAA,PCT,and HMGB1 Levels as potential diagnostic markers.The combined model of the three biomarkers demonstrating an extremely high area under the curve(0.908).CONCLUSION The diagnostic value of serum SAA,PCT,and HMGB1 Levels in NEC was highlighted.These biomarkers potentially improve the early detection,risk stratification,and clinical management of critical conditions.The findings suggest that these biomarkers may aid in timely intervention and the enhancement of outcomes for neonates affected by NEC.
文摘The use of anticoagulation therapy could prove to be controversial when trying to balance ischemic stroke and intracranial bleeding risks in patients with concurrent cerebral amyloid angiopathy(CAA)and atrial fibrillation(AF).In fact,CAA is an age-related cerebral vasculopathy that predisposes patients to intracerebral hemorrhage.Nevertheless,many AF patients require oral systemic dose-adjusted warfarin,direct oral anticoagulants(such as factor Xa inhibitors)or direct thrombin inhibitors to control often associated with cardioembolic stroke risk.The prevalence of both CAA and AF is expected to rise,due to the aging of the population.This clinical dilemma is becoming increasingly common.In patients with coexisting AF and CAA,the risks/benefits profile of anticoagulant therapy must be assessed for each patient individually due to the lack of a clear-cut consensus with regard to its risks in scientific literature.This review aims to provide an overview of the management of patients with concomitant AF and CAA and proposes the implementation of a risk-based decision-making algorithm.
文摘Increasing evidence demonstrated that the blood-brain barrier(BBB)was involved in developing cerebral amyloid angiopathy(CAA).The BBB participates in the neurovascular coupling and regulates the transport of substances,which is closely related to neurodegenerative diseases.In CAA,the deposition of amyloid beta(Aβ)in arteries,capillaries,and arterioles of meninges and cerebral cortex results in the destruction of the BBB,chronic inflammatory response,chronic cerebral hypoperfusion,and dysfunction of the neurovascular unit,which eventually leads to neurodegeneration.At the same time,CAA is an age-related disease.Patients with CAA often have some risk factors for cerebrovascular diseases,such as hypertension and diabetes,which can further aggravate the damage to the BBB.Thus,it is of great significance to pay attention to the BBB in the pathogenesis and future intervention targets of CAA.Therefore,this manuscript reviewed the dysfunction of the BBB in CAA.
基金funded by the National Natural Science Foundation of China(82372018 and 81701753)The Beijing Natural Science Foundation(7222299)+1 种基金Beijing Medical Authority Cultivation Program(PX2022035)Medical Innovation Capability Improvement Plan of Capital Medical University(12300124).
文摘Cerebral amyloid angiopathy(CAA)is a small vessel disease of the brain characterized by the progressive deposition of amyloid-β(Aβ)plaques in the walls of cerebral blood vessels.It presents with a subtle course and sudden onset,and currently,there are no specific therapeutic interventions available.Accurate diagnosis of CAA could enable targeted interventions in the early stages of the disease,potentially mitigating the disease’s effects.Herein,we review the primary imaging biomarkers used in the diagnosis of CAA,including their mechanisms,imaging characteristics,and significance.We also provide an interpretation of the latest version(v2.0)of the Boston criteria,which are commonly used in the clinical diagnosis of CAA.Additionally,this study introduces various positron emission tomography(PET)tracers for CAA and reviews their application values in the diagnosis of CAA.
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.
文摘Objective: To construct a PC12 cell strain with neuronal differentiation, and observe the apoptosis and pro- liferation activity effects induced these cells by Amyloid beta-Protein (Aβ-43). Methods: 1) PC12 cells in logarithmic growth phase were subcultured for 24 h. After the culture fluid was changed, the cells were treated with Rat-β-NGF and cultured for 9 days. 2) Neuronal differentiation of PC12 cells in logarithmic growth phase were divided into four groups: control group (0), experimental group (1), experimental group (2) and experimental group (3). The concentrations of Aβ in the four groups were 0 μmol/L, 1.25 μmol/L, 2.5 μmol/L and 5 μmol/L, respectively. The cells were harvested at 24, 48 and 72 h later and stained with AnnexinV-FITC/PI after centrifugation and washing. Then flow cytometry was conducted to examine the apoptosis percentage. 3) NGF-induced PC12 cells were selected and Aβ with different concentrations was added. The final concentrations of Aβ were 0 μmol/L, 1.25 μmol/L, 2.5 μmol/L and 5 μmol/L, respectively. After the cells were incubated in an atmosphere of 5% CO2 at 37 °C in an incubator for 72 h, the OD values were examined. Results: 1) Neuronal differentiated PC12 cell lines were successfully established. 2) Flow cytometric examination indicated that Aβ (1.25, 2.5, and 5.0 μmol/L) could effectively induce apoptosis of neuronal-differented cells at the 24 h, 48 h and 72 h time points. 3) Aβ (0?5.00 μmol/L) had no obvious effect on proliferation or restraining of the neuronal differentiation of the PC12 cells after a 72 h interacting process. Conclusion: This investigation revealed successful neuronal differentiation of the PC12 cell strain. The induction of apoptosis of the neurocytes by various concentrations of Aβ was observed and the in- fluence of Aβ on induced proliferation of PC12 cells by Rat-β-NGF was revealed. This study may provide basis for future research on the molecular cure of AD and interdiction of AD evolution.
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.
文摘BACKGROUND： The findings about the alterations in cerebrospinal fluid beta-amyloid protein （Aβ ） and apolipoprotein E （APOE） after subarachnoid hemorrhage indicate that they have significant correlation with prognosis of patients. OBJECTⅣE： To observe the alterations in cerebrospinal fluid Aβ and ApoE after subarachnoid hemorrhage （SAH）. DESIGN： Contrast observation. SETTING： Department of Neurosurgery, the First Hospital of Lanzhou University. PARTICIPANTS： A total of 25 SAH patients including 16 males and 9 females aged from 13 to 72 years were selected form Department of Neurosurgery, the First Affiliated Hospital of Lanzhou University from October 2003 to February 2004. The Hunt-Hess grade ranged from Ⅰ to Ⅳ, and patients admitted hospital in 24 hours after invasion, affirmed by the brain CT scan and lumbar vertebra puncture, no other severe complications and important organs＇ functional defect and severe infection, no hematological system disease. METHODS- All admitted patients were collected CSF by lumbar vertebra puncture in 24 hours. The cerebrospinal fluid （CSF） of control group came from the admitted 15 patients of our hospital that have no nervous system disease. Aβ content was detected by enzyme linked immunosorbent assay （ELISA）, the kit was provided by the Central Laboratory of the First Hospital of Lanzhou University; ApoE concentration was detected by monoclone enzyme linked immunosorbent assay （ELISA）, the kit was provided by the Immunotechnique Research Institute of the Fourth Military Medical University. S100B concentration was detected by enzyme linked immunosorbent assay double antibody sandwich method, the kit was provided by the Physiological Research Room of the Fourth Military Medical University. The data were indicated on Mean±SD and were analyzed by SPSS 10.0 statistical package. All data were handled through test of significance variance analysis, and groups were compared through independent sampler t test. The concentration was handled through Pearson correlation analysis between Aβ and ApoE. The relationship between Aβ, ApoE concentration with pathogenetic condition and prognosis of the patients was handled through Spearman ranking correlation analysis. MAIN OUTCOME MEASURES：① The concentration of ApoE, Aβ and S100B after SAH in contrast to the control group in CSF by different Hunt-Hess and Glasgow Outcome Scale （GOS） grades; ② The level of correlation between ApoE and Aβ ; ③Correlation between ApoE and Aβ in pathogenetic condition and prognosis of the patients. RESULTS： All 25 SAH patients and 15 controls were involved in the final analysis. ① The concentration of ApoE, Aβ and S100B in CSF： The concentration of ApoE decreased after SAH in contrast to the control group [（0.46±0.007）, （0.85±0.11） μg/L, P 〈 0.01], the concentration of ApoE decreased after SAH in contrast to the control group [（5.36± 1.19）, （8.41± 1.60） μg/L, P 〈 0.01], and the concentration of S100B increased after SAH in contrast to the control group [（18.60±7.31）, （6.56±1.02） pg/L, P 〈 0.01]. ② The concentration of ApoE, Aβ and S100B in CSF after SAH on different Hunt-Hess and GOS grades： The concentration of Aβ in Hunt-Hess Ⅰ -Ⅲ grade was higher than Hunt-Hess Ⅳ, Ⅴ grade [（6.63 ± 1.25）, （3.35± 1.02） μg/L, P 〈 0.01], and the concentration of ApoE in Hunt-Hess Ⅰ- Ⅲ grade was higher than Hunt-Hess Ⅳ, Ⅴ grade [（0.56±0.07）, （0.38±0.04） μg/L, P 〈 0.05], the concentration of S100B in Hunt-Hess Ⅰ - Ⅲ grade was lower than Hunt-Hess Ⅳ - Ⅴ grade [（16.32±5.58）, （22.85±8.10） pg/L, P 〈 0.01]; the concentration of Aβ in GOS Ⅰ - Ⅲ grade was lower than GOS Ⅳ, Ⅴ grade [（3.76± 1.04）, （5.89±1.20） μg/L, P 〈 0.01], and the concentration of ApoE in GOS Ⅰ - Ⅲ grade was lower than GOS Ⅳ, Ⅴ grade [（0.32±0.02）, （0.58±0.07） μg/L, P 〈 0.011, and the concentration of S100B in GOS Ⅰ - Ⅲ grade was higher than GOS Ⅳ, Ⅴ grade [（25.36±9.70）, （14.33±6.69） pg/L, P 〈 0.01].③ The results of Pearson correlation analysis and Spearman ranking correlation analysis： There was significantly positive correlation between CSF Aβ concentration and clinical outcome （r=0.65, P 〈 0.01）, and the decrease in CSF Aβ concentration correlated significant with that of ApoE （r =0.85, P 〈 0.01）. CONCLUSION： There is a significant decrease in both Aβ and ApoE in the CSF after SAH, and there is significant correlation between CSF Aβ and ApoE concentration with clinical outcome, the interactions between these proteins may have important effects on SAH, ApoE and Aβ as surrogate markers for the outcome of patients with SAH.
文摘Aim: The abnormal accumulation, assembly and deposition of the amyloid β-protein (Aβ) are prominent pathological features of patients with Alzheimer’s disease (AD) and related disorders. A number of factors in the brain can influence Aβ accumulation and associated pathologies. The aim of the present study was to determine the consequences of deleting nitric oxide synthase (NOS) 3, the endothelial form of NOS, in Tg-5xFAD mice, a model of parenchymal AD-like amyloid pathology. Methods: Tg-5xFAD mice were bred with NOS3-/- mice. Cohorts of Tg-5xFAD mice and bigenic Tg-5xFAD/NOS3-/- mice were aged to six months followed by collection of the blood and brain tissues from the mice for biochemical and pathological analyses. Results: ELISA analyses show that the absence of NOS3 results in elevated levels of cerebral and plasma Aβ peptides in Tg-5xFAD mice. Immunohistochemical analyses show that the absence of NOS3 increased the amount of parenchymal Aβ deposition and fibrillar amyloid accumulation in Tg-5xFAD mice. The elevated levels of Aβ were not due to changes in the expression levels of transgene encoded human amyloid precursor protein (APP), endogenous β-secretase, or increased proteolytic processing of APP. Conclusions: The results from this study suggest that the loss of NOS3 activity enhances Aβ pathology in Tg-5xFAD mice. These findings are similar to previous studies of NOS2 deletion suggesting that reduced NOS activity and NO levels enhance amyloid-associated pathologies in human APP transgenic mice.
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.
