Alzheimer’s disease(AD)is a slow,progressive neurodegenerative disease with clinical symptoms that typically emerge in the elderly,leading to deterioration of cognitive functions over time.Memory loss is the primary ...Alzheimer’s disease(AD)is a slow,progressive neurodegenerative disease with clinical symptoms that typically emerge in the elderly,leading to deterioration of cognitive functions over time.Memory loss is the primary symptom,eventually leading to significant declines in executive and cognitive functions,along with psychiatric and behavioral changes,and alterations in personality.展开更多
Deficits in the clearance of amyloidβprotein(Aβ)by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer’s disease(AD).Impaired uptake of Aβby dysfunctional monocytes is deemed to be...Deficits in the clearance of amyloidβprotein(Aβ)by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer’s disease(AD).Impaired uptake of Aβby dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aβclearance in AD.In the current study,flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin(PSK)on AD-related pathology in vitro and in vivo.We found that PSK,widely used in therapy for various cancers,has the potential to enhance Aβuptake and intracellular processing by human monocytes in vitro.After administration of PSK by intraperitoneal injection,APP/PS1 mice performed better in behavioral tests,along with reduced Aβdeposition,neuroinflammation,neuronal loss,and tau hyperphosphorylation.These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aβclearance by blood monocytes and alleviating AD-like pathology.展开更多
Increased neuronal apoptosis is an important pathological feature of Alzheimer’s disease(AD).The Bcl-2-interacting mediator of cell death(Bim)mediates amyloid-beta(Aβ)-induced neuronal apoptosis.Naturally-occurring ...Increased neuronal apoptosis is an important pathological feature of Alzheimer’s disease(AD).The Bcl-2-interacting mediator of cell death(Bim)mediates amyloid-beta(Aβ)-induced neuronal apoptosis.Naturally-occurring antibodies against Bim(NAbs-Bim)exist in human blood,with their levels and functions unknown in AD.In this study,we found that circulating NAbs-Bim were decreased in AD patients.Plasma levels of NAbs-Bim were negatively associated with brain amyloid burden and positively associated with cognitive functions.Furthermore,NAbs-Bim purified from intravenous immunoglobulin rescued the behavioral deficits and ameliorated Aβdeposition,tau hyperphosphorylation,microgliosis,and neuronal apoptosis in APP/PS1 mice.In vitro investigations demonstrated that NAbs-Bim were neuroprotective against AD through neutralizing Bim-directed neuronal apoptosis and the amyloidogenic processing of amyloid precursor protein.These findings indicate that the decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim hold promise for the treatment of AD.展开更多
Deficiencies in the clearance of peripheral amyloidβ(Aβ)play a crucial role in the progression of Alzheimer’s disease(AD).Previous studies have shown that the ability of blood monocytes to phagocytose Aβis decreas...Deficiencies in the clearance of peripheral amyloidβ(Aβ)play a crucial role in the progression of Alzheimer’s disease(AD).Previous studies have shown that the ability of blood monocytes to phagocytose Aβis decreased in AD.However,the exact mechanism of Aβclearance dysfunction in AD monocytes remains unclear.In the present study,we found that blood monocytes in AD mice exhibited decreases in energy metabolism,which was accompanied by cellular senescence,a senescence-associated secretory phenotype,and dysfunctional phagocytosis of Aβ.Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβin vivo and in vitro.Moreover,enhancing blood monocyte Aβphagocytosis by improving energy metabolism alleviated brain Aβdeposition and neuroinflammation and eventually improved cognitive function in AD mice.This study reveals a new mechanism of impaired Aβphagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.展开更多
The extracellular domain(p75ECD)of p75 neurotrophin receptor(p75NTR)antagonizes Aβ neurotoxicity and promotes Aβclearance in Alzheimer’s disease(AD).The impaired shedding of p75ECD is a key pathological process in ...The extracellular domain(p75ECD)of p75 neurotrophin receptor(p75NTR)antagonizes Aβ neurotoxicity and promotes Aβclearance in Alzheimer’s disease(AD).The impaired shedding of p75ECD is a key pathological process in AD,but its regulatory mechanism is largely unknown.This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD(p75ECD-NAbs)in AD patients and their effects on AD pathology.We found that the cerebrospinal fluid(CSF)level of p75ECD-NAbs was increased in AD,and negatively associated with the CSF levels of p75ECD.Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain,as well as worse cognitive functions than the control groups,which were immunized with Re-p75ECD(the reverse sequence of p75ECD)and phosphate-buffered saline,respectively.These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance,providing a novel insight into the role of autoimmunity and p75NTR in AD.展开更多
Ischemic stroke is the leading cause of death in the Chinese population.The incidence of cerebral infarction is higher in high-altitude regions,particularly those above 3,500 m,than in populations residing at lower al...Ischemic stroke is the leading cause of death in the Chinese population.The incidence of cerebral infarction is higher in high-altitude regions,particularly those above 3,500 m,than in populations residing at lower altitudes[1].There are various speculations regarding the mechanisms behind this phenomenon,one of which is that the low oxygen content and cold climate at high altitudes may increase the occurrence of vascular diseases[2].The multifactorial effect of high-altitude environments on residential populations makes it challenging for researchers to determine the specific pathways through which these diseases occur.展开更多
Alzheimer's disease(AD)is a neurodegenerative disease that increasingly burdens many families worldwide.Although AD is generally thought to be closely associated with gray matter,many studies have identified signi...Alzheimer's disease(AD)is a neurodegenerative disease that increasingly burdens many families worldwide.Although AD is generally thought to be closely associated with gray matter,many studies have identified significant changes in white matter as well,including demyelination and function alterations in oligodendrocytes in the AD brain.In addition,Ap plaques,the most important pathological characteristic in AD,are deposited in late-myelinating regions such as the prefrontal and temporal lobes,where myelin is prone to damage[1].All the evidence hints that the changes in myelin are closely associated with the onset and progression of AD,prompting scientists to outline the process of changing myelin in AD and develop novel strategies for the treatment of AD.展开更多
Alzheimer's disease(AD)is the most common type of dementia that imposes a high burden on caregivers and has substantial economic cost for society.Although there are no drugs available to reverse the progression of...Alzheimer's disease(AD)is the most common type of dementia that imposes a high burden on caregivers and has substantial economic cost for society.Although there are no drugs available to reverse the progression of AD,a large number of studies have shown that intervention for the risk factors for AD or administration of disease-modifying therapy at the preclinical/prodromal stage yields better outcomes.Therefore,early diagnosis or accurate prediction of AD in healthy populations and preclinical AD is an important prerequisite for effective intervention.展开更多
In the context of global ageing,the prevalence of neurodegenerative diseases and dementia,such as Alzheimer's disease(AD),is increasing.However,the current symptomatic and disease-modifying therapies have achieved...In the context of global ageing,the prevalence of neurodegenerative diseases and dementia,such as Alzheimer's disease(AD),is increasing.However,the current symptomatic and disease-modifying therapies have achieved limited benefits for neurodegenerative diseases in clinical settings.Halting the progress of neurodegeneration and cognitive decline or even improving impaired cognition and function are the clinically meaningful goals of treatments for neurodegenerative diseases.Ageing is the primary risk factor for neurodegenerative diseases and their associated comorbidities,such as vascular pathologies,in elderly individuals.Thus,we aim to elucidate the role of ageing in neurodegenerative diseases from the perspective of a complex system,in which the brain is the core and peripheral organs and tissues form a holistic network to support brain functions.During ageing,the progressive deterioration of the structure and function of the entire body hampers its active and adaptive responses to various stimuli,thereby rendering individuals more vulnerable to neurodegenerative diseases.Consequently,we propose that the prevention and treatment of neurodegenerative diseases should be grounded in holistic antiageing and rejuvenation means complemented by interventions targeting disease-specific pathogenic events.This integrated approach is a promising strategy to effectively prevent,pause or slow down the progression of neurodegenerative diseases.展开更多
In the context of rapid societal ageing,the analysis and address of ageing have become increasingly imperative.Ageing is characterized by the accumulation of molecular,cellular,and organ damage,leading to systemic fun...In the context of rapid societal ageing,the analysis and address of ageing have become increasingly imperative.Ageing is characterized by the accumulation of molecular,cellular,and organ damage,leading to systemic functional decline and increased disease susceptibility.展开更多
Systemic factors confound blood tests for the diagnosis of Alzheimer’s disease(AD).The Delta Method study explored whether blood biomarkers from the vein proximal to the brain perform better in detecting cerebral Alz...Systemic factors confound blood tests for the diagnosis of Alzheimer’s disease(AD).The Delta Method study explored whether blood biomarkers from the vein proximal to the brain perform better in detecting cerebral Alzheimer’s pathologies using PET or cerebrospinal fluid(CSF)biomarkers as reference standards in two independent cohorts(n=463).Blood was collected from the internal jugular vein(IJV)and median cubital vein(MCV),and AD biomarkers were measured with Lumipulse G and Simoa methods.The results showed that the levels of Aβ42,Aβ40,p-tau217,p-tau181,GFAP,and NfL were higher in the IJV than in MCV and were highly correlated between the two sites.IJV-Aβ42/40 had stronger correlations with AβPET Centiloids and tau PET meta-temporal SUVR than MCV-Aβ42/40.In detecting cerebral Aβpositivity,IJV-Aβ42/40 demonstrated a significantly higher accuracy(79.9%–92.9%vs.72.4%–88.8%)and a lower percentage of uncertain individuals(17.8%–54.5%vs.31.3%–70.1%)than MCV-Aβ42/40.Moreover,the diagnostic accuracy of Lumipulse G IJV-Aβ42/40(88.2%–92.9%)was statistically equivalent to that of MCV-p-tau217(90.2%–94.3%),although the intermediate percentage of IJV-Aβ42/40 was higher(17.8%–34.0%vs.0.7%–17.5%).These findings were verified in the validation cohort.This study demonstrated the superior performance of IJV-Aβ42/40 to MCV-Aβ42/40 in detecting cerebral Alzheimer’s pathologies,offering a novel perspective to reduce the impacts of systemic factors and comorbidities on blood tests.展开更多
More than 2 million new ischemic stroke patients are diagnosed every year in China,with a prevalence of about11 million.Stroke is the leading cause of death in the country[1,2].The therapeutic effect on ischemic strok...More than 2 million new ischemic stroke patients are diagnosed every year in China,with a prevalence of about11 million.Stroke is the leading cause of death in the country[1,2].The therapeutic effect on ischemic stroke in the ultra-early period depends on the timely restoration of the blood supply to rescue brain tissue.展开更多
Background:Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease(AD).However,there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pa...Background:Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease(AD).However,there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pathology.We investigated the effect of chronic cerebral hypoperfusion on AD-related pathology in humans.Methods:We enrolled a group of cognitively normal patients(median age:64 years)with unilateral chronic cerebral hypoperfusion.Regions of interest with the most pronounced hypoperfusion changes were chosen in the hypoperfused region and were then mirrored in the contralateral hemisphere to create a control region with normal perfusion.11C-Pittsburgh compound-positron emission tomography standard uptake ratios and brain atrophy indices were calculated from the computed tomography images of each patient.Results:The median age of the 10 participants,consisting of 4 males and 6 females,was 64 years(47-76 years).We found that there were no differences in standard uptake ratios of the cortex(volume of interest[VOI]:P=0.721,region of interest[ROI]:P=0.241)and grey/white ratio(VOI:P=0.333,ROI:P=0.445)and brain atrophy indices(Bicaudate,Bifrontal,Evans,Cella,Cella media,and Ventricular index,P>0.05)between the hypoperfused regions and contralateral normally perfused regions in patients with unilateral chronic cerebral hypoperfusion.Conclusion:Our findings suggest that chronic hypoperfusion due to large vessel stenosis may not directly induce cerebralβ-amyloid deposition and neurodegeneration in humans.展开更多
Aging is the primary risk factor for various chronic disorders,especially neurodegeneration diseases,including Alzheimer’s disease(AD)and Parkinson’s disease(PD).It has been estimated that about one in ten individua...Aging is the primary risk factor for various chronic disorders,especially neurodegeneration diseases,including Alzheimer’s disease(AD)and Parkinson’s disease(PD).It has been estimated that about one in ten individuals aged>65 are affected by AD,and this prevalence continues to increase with the aging of the population[1],causing a heavy burden on the family and society.As the aging population grows progressively around the globe,drug discoveries targeting the aging process have become a hot spot[2].展开更多
Amyloid-beta(Aβ)plays a pivotal role in the pathogenesis of Alzheimer's disease(AD)and has been regarded as the main therapeutic target for AD.However,most of the Aβ-targeted clinical trials have not succeeded.T...Amyloid-beta(Aβ)plays a pivotal role in the pathogenesis of Alzheimer's disease(AD)and has been regarded as the main therapeutic target for AD.However,most of the Aβ-targeted clinical trials have not succeeded.Therefore,the Aβ-targeted therapeutic strategy on treating this complex disease needs to be re-evaluated.In this review,we analyzed the challenges and critical points of the current anti-Aβtherapeutic strategies.In addition to Aβ,multiple pathological events such as tau hyperphosphorylation,oxidative stress,and neuroinflammation,which are involved in AD pathogenesis and synergistically drive disease progression,could be important targets for AD treatment.Tertiary prevention strategies are needed for the successful management of AD due to its complex and dynamic pathogenesis.Systemic perspective addressing the disease pathogenesis within and outside the brain,as well as the multidomain intervention targeting risk factors and comorbidities,are important approaches for the therapeutic solutions of AD.展开更多
The aetiologies and origins of neurodegenerative diseases,such as Alzheimer’s disease(AD),Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS)and Huntington’s disease(HD),are complex and multifaceted.A growin...The aetiologies and origins of neurodegenerative diseases,such as Alzheimer’s disease(AD),Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS)and Huntington’s disease(HD),are complex and multifaceted.A growing body of evidence suggests that the gut microbiome plays crucial roles in the development and progression of neurodegenerative diseases.Clinicians have come to realize that therapeutics targeting the gut microbiome have the potential to halt the progression of neurodegenerative diseases.This narrative review examines the alterations in the gut microbiome in AD,PD,ALS and HD,highlighting the close relationship between the gut microbiome and the brain in neurodegenerative diseases.Processes that mediate the gut microbiome-brain communication in neurodegenerative diseases,including the immunological,vagus nerve and circulatory pathways,are evaluated.Furthermore,we summarize potential therapeutics for neurodegenerative diseases that modify the gut microbiome and its metabolites,including diets,probiotics and prebiotics,microbial metabolites,antibacterials and faecal microbiome transplantation.Finally,current challenges and future directions are discussed.展开更多
The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a s...The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.展开更多
基金supported by the National Natural Science Foundation of China(82120108010 and 81930028).
文摘Alzheimer’s disease(AD)is a slow,progressive neurodegenerative disease with clinical symptoms that typically emerge in the elderly,leading to deterioration of cognitive functions over time.Memory loss is the primary symptom,eventually leading to significant declines in executive and cognitive functions,along with psychiatric and behavioral changes,and alterations in personality.
基金the National Natural Science Foundation of China(81930028,91749206,81625007,and 31921003).
文摘Deficits in the clearance of amyloidβprotein(Aβ)by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer’s disease(AD).Impaired uptake of Aβby dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aβclearance in AD.In the current study,flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin(PSK)on AD-related pathology in vitro and in vivo.We found that PSK,widely used in therapy for various cancers,has the potential to enhance Aβuptake and intracellular processing by human monocytes in vitro.After administration of PSK by intraperitoneal injection,APP/PS1 mice performed better in behavioral tests,along with reduced Aβdeposition,neuroinflammation,neuronal loss,and tau hyperphosphorylation.These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aβclearance by blood monocytes and alleviating AD-like pathology.
基金supported by the National Natural Science Foundation of China(81930028,81971024,and 81971033).
文摘Increased neuronal apoptosis is an important pathological feature of Alzheimer’s disease(AD).The Bcl-2-interacting mediator of cell death(Bim)mediates amyloid-beta(Aβ)-induced neuronal apoptosis.Naturally-occurring antibodies against Bim(NAbs-Bim)exist in human blood,with their levels and functions unknown in AD.In this study,we found that circulating NAbs-Bim were decreased in AD patients.Plasma levels of NAbs-Bim were negatively associated with brain amyloid burden and positively associated with cognitive functions.Furthermore,NAbs-Bim purified from intravenous immunoglobulin rescued the behavioral deficits and ameliorated Aβdeposition,tau hyperphosphorylation,microgliosis,and neuronal apoptosis in APP/PS1 mice.In vitro investigations demonstrated that NAbs-Bim were neuroprotective against AD through neutralizing Bim-directed neuronal apoptosis and the amyloidogenic processing of amyloid precursor protein.These findings indicate that the decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim hold promise for the treatment of AD.
基金supported by the National Natural Science Foundation of China(82122023 and U22A20294).
文摘Deficiencies in the clearance of peripheral amyloidβ(Aβ)play a crucial role in the progression of Alzheimer’s disease(AD).Previous studies have shown that the ability of blood monocytes to phagocytose Aβis decreased in AD.However,the exact mechanism of Aβclearance dysfunction in AD monocytes remains unclear.In the present study,we found that blood monocytes in AD mice exhibited decreases in energy metabolism,which was accompanied by cellular senescence,a senescence-associated secretory phenotype,and dysfunctional phagocytosis of Aβ.Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβin vivo and in vitro.Moreover,enhancing blood monocyte Aβphagocytosis by improving energy metabolism alleviated brain Aβdeposition and neuroinflammation and eventually improved cognitive function in AD mice.This study reveals a new mechanism of impaired Aβphagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.
基金supported by the National Natural Science Foundation of China(81870860).
文摘The extracellular domain(p75ECD)of p75 neurotrophin receptor(p75NTR)antagonizes Aβ neurotoxicity and promotes Aβclearance in Alzheimer’s disease(AD).The impaired shedding of p75ECD is a key pathological process in AD,but its regulatory mechanism is largely unknown.This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD(p75ECD-NAbs)in AD patients and their effects on AD pathology.We found that the cerebrospinal fluid(CSF)level of p75ECD-NAbs was increased in AD,and negatively associated with the CSF levels of p75ECD.Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain,as well as worse cognitive functions than the control groups,which were immunized with Re-p75ECD(the reverse sequence of p75ECD)and phosphate-buffered saline,respectively.These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance,providing a novel insight into the role of autoimmunity and p75NTR in AD.
基金supported by the National Natural Science Foundation of Chongqing,China(CSTB2022NSCQ-MSX1100)National Natural Science Foundation of China(grant no.82101499).
文摘Ischemic stroke is the leading cause of death in the Chinese population.The incidence of cerebral infarction is higher in high-altitude regions,particularly those above 3,500 m,than in populations residing at lower altitudes[1].There are various speculations regarding the mechanisms behind this phenomenon,one of which is that the low oxygen content and cold climate at high altitudes may increase the occurrence of vascular diseases[2].The multifactorial effect of high-altitude environments on residential populations makes it challenging for researchers to determine the specific pathways through which these diseases occur.
基金National Natural Science Foundation of China(81930028,31921003,91749206,and 81625007)。
文摘Alzheimer's disease(AD)is a neurodegenerative disease that increasingly burdens many families worldwide.Although AD is generally thought to be closely associated with gray matter,many studies have identified significant changes in white matter as well,including demyelination and function alterations in oligodendrocytes in the AD brain.In addition,Ap plaques,the most important pathological characteristic in AD,are deposited in late-myelinating regions such as the prefrontal and temporal lobes,where myelin is prone to damage[1].All the evidence hints that the changes in myelin are closely associated with the onset and progression of AD,prompting scientists to outline the process of changing myelin in AD and develop novel strategies for the treatment of AD.
基金This Research Highlight was supported by the National Natural Science Foundation of China(82122023)the Natural Science Foundation of Chongqing,China(cstc2020jcyj-msxmX0132).
文摘Alzheimer's disease(AD)is the most common type of dementia that imposes a high burden on caregivers and has substantial economic cost for society.Although there are no drugs available to reverse the progression of AD,a large number of studies have shown that intervention for the risk factors for AD or administration of disease-modifying therapy at the preclinical/prodromal stage yields better outcomes.Therefore,early diagnosis or accurate prediction of AD in healthy populations and preclinical AD is an important prerequisite for effective intervention.
基金supported by the National Key Research and Development Program Foundation of China(2023YFC3605400)Natural Science Foundation of China(92249305,82171418).
文摘In the context of global ageing,the prevalence of neurodegenerative diseases and dementia,such as Alzheimer's disease(AD),is increasing.However,the current symptomatic and disease-modifying therapies have achieved limited benefits for neurodegenerative diseases in clinical settings.Halting the progress of neurodegeneration and cognitive decline or even improving impaired cognition and function are the clinically meaningful goals of treatments for neurodegenerative diseases.Ageing is the primary risk factor for neurodegenerative diseases and their associated comorbidities,such as vascular pathologies,in elderly individuals.Thus,we aim to elucidate the role of ageing in neurodegenerative diseases from the perspective of a complex system,in which the brain is the core and peripheral organs and tissues form a holistic network to support brain functions.During ageing,the progressive deterioration of the structure and function of the entire body hampers its active and adaptive responses to various stimuli,thereby rendering individuals more vulnerable to neurodegenerative diseases.Consequently,we propose that the prevention and treatment of neurodegenerative diseases should be grounded in holistic antiageing and rejuvenation means complemented by interventions targeting disease-specific pathogenic events.This integrated approach is a promising strategy to effectively prevent,pause or slow down the progression of neurodegenerative diseases.
基金supported by the National Key Research and Development Program of China(2023YFC3605400)the Commission of Chongqing Municipality(2024GGXM003)。
文摘In the context of rapid societal ageing,the analysis and address of ageing have become increasingly imperative.Ageing is characterized by the accumulation of molecular,cellular,and organ damage,leading to systemic functional decline and increased disease susceptibility.
基金supported by the National Key Research and Development Program of China(2023YFC3605400)the Joint Project of the Chongqing Science and Technology Bureau and the Health Commission(2024GGXM003)。
文摘Systemic factors confound blood tests for the diagnosis of Alzheimer’s disease(AD).The Delta Method study explored whether blood biomarkers from the vein proximal to the brain perform better in detecting cerebral Alzheimer’s pathologies using PET or cerebrospinal fluid(CSF)biomarkers as reference standards in two independent cohorts(n=463).Blood was collected from the internal jugular vein(IJV)and median cubital vein(MCV),and AD biomarkers were measured with Lumipulse G and Simoa methods.The results showed that the levels of Aβ42,Aβ40,p-tau217,p-tau181,GFAP,and NfL were higher in the IJV than in MCV and were highly correlated between the two sites.IJV-Aβ42/40 had stronger correlations with AβPET Centiloids and tau PET meta-temporal SUVR than MCV-Aβ42/40.In detecting cerebral Aβpositivity,IJV-Aβ42/40 demonstrated a significantly higher accuracy(79.9%–92.9%vs.72.4%–88.8%)and a lower percentage of uncertain individuals(17.8%–54.5%vs.31.3%–70.1%)than MCV-Aβ42/40.Moreover,the diagnostic accuracy of Lumipulse G IJV-Aβ42/40(88.2%–92.9%)was statistically equivalent to that of MCV-p-tau217(90.2%–94.3%),although the intermediate percentage of IJV-Aβ42/40 was higher(17.8%–34.0%vs.0.7%–17.5%).These findings were verified in the validation cohort.This study demonstrated the superior performance of IJV-Aβ42/40 to MCV-Aβ42/40 in detecting cerebral Alzheimer’s pathologies,offering a novel perspective to reduce the impacts of systemic factors and comorbidities on blood tests.
基金the Clinical Medical Research Expert Training Program of Daping Hospital,China(2018XLC2022)。
文摘More than 2 million new ischemic stroke patients are diagnosed every year in China,with a prevalence of about11 million.Stroke is the leading cause of death in the country[1,2].The therapeutic effect on ischemic stroke in the ultra-early period depends on the timely restoration of the blood supply to rescue brain tissue.
文摘Background:Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease(AD).However,there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pathology.We investigated the effect of chronic cerebral hypoperfusion on AD-related pathology in humans.Methods:We enrolled a group of cognitively normal patients(median age:64 years)with unilateral chronic cerebral hypoperfusion.Regions of interest with the most pronounced hypoperfusion changes were chosen in the hypoperfused region and were then mirrored in the contralateral hemisphere to create a control region with normal perfusion.11C-Pittsburgh compound-positron emission tomography standard uptake ratios and brain atrophy indices were calculated from the computed tomography images of each patient.Results:The median age of the 10 participants,consisting of 4 males and 6 females,was 64 years(47-76 years).We found that there were no differences in standard uptake ratios of the cortex(volume of interest[VOI]:P=0.721,region of interest[ROI]:P=0.241)and grey/white ratio(VOI:P=0.333,ROI:P=0.445)and brain atrophy indices(Bicaudate,Bifrontal,Evans,Cella,Cella media,and Ventricular index,P>0.05)between the hypoperfused regions and contralateral normally perfused regions in patients with unilateral chronic cerebral hypoperfusion.Conclusion:Our findings suggest that chronic hypoperfusion due to large vessel stenosis may not directly induce cerebralβ-amyloid deposition and neurodegeneration in humans.
基金This highlight was supported by the National Natural Science Foundation of China(91749206 and 81930028).
文摘Aging is the primary risk factor for various chronic disorders,especially neurodegeneration diseases,including Alzheimer’s disease(AD)and Parkinson’s disease(PD).It has been estimated that about one in ten individuals aged>65 are affected by AD,and this prevalence continues to increase with the aging of the population[1],causing a heavy burden on the family and society.As the aging population grows progressively around the globe,drug discoveries targeting the aging process have become a hot spot[2].
基金supported by the National Natural Science Foundation of China(91749206,81930028,81625007,81870860,31921003)。
文摘Amyloid-beta(Aβ)plays a pivotal role in the pathogenesis of Alzheimer's disease(AD)and has been regarded as the main therapeutic target for AD.However,most of the Aβ-targeted clinical trials have not succeeded.Therefore,the Aβ-targeted therapeutic strategy on treating this complex disease needs to be re-evaluated.In this review,we analyzed the challenges and critical points of the current anti-Aβtherapeutic strategies.In addition to Aβ,multiple pathological events such as tau hyperphosphorylation,oxidative stress,and neuroinflammation,which are involved in AD pathogenesis and synergistically drive disease progression,could be important targets for AD treatment.Tertiary prevention strategies are needed for the successful management of AD due to its complex and dynamic pathogenesis.Systemic perspective addressing the disease pathogenesis within and outside the brain,as well as the multidomain intervention targeting risk factors and comorbidities,are important approaches for the therapeutic solutions of AD.
基金supported by the National Natural Science Foundation of China(92249305)and the Special Funding for Chongqing Postdoctoral Research Project.
文摘The aetiologies and origins of neurodegenerative diseases,such as Alzheimer’s disease(AD),Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS)and Huntington’s disease(HD),are complex and multifaceted.A growing body of evidence suggests that the gut microbiome plays crucial roles in the development and progression of neurodegenerative diseases.Clinicians have come to realize that therapeutics targeting the gut microbiome have the potential to halt the progression of neurodegenerative diseases.This narrative review examines the alterations in the gut microbiome in AD,PD,ALS and HD,highlighting the close relationship between the gut microbiome and the brain in neurodegenerative diseases.Processes that mediate the gut microbiome-brain communication in neurodegenerative diseases,including the immunological,vagus nerve and circulatory pathways,are evaluated.Furthermore,we summarize potential therapeutics for neurodegenerative diseases that modify the gut microbiome and its metabolites,including diets,probiotics and prebiotics,microbial metabolites,antibacterials and faecal microbiome transplantation.Finally,current challenges and future directions are discussed.
基金National Natural Science Foundation of China,Grant/Award Numbers:92249305,82120108010,81930028,31921003Academy of Medical Sciences(Newton Advanced Fellowship),Grant/Award Number:NAF/R11/1010National Institutes of Health,Grant/Award Number:R01DA056739。
文摘The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.
