Neuroinflammation was linked to neu-rodegenerative diseases long ago,but no related treatment has proven effective.A new study unveils the inflammatory links between microglia and cognitive decline,providing new idea ...Neuroinflammation was linked to neu-rodegenerative diseases long ago,but no related treatment has proven effective.A new study unveils the inflammatory links between microglia and cognitive decline,providing new idea for the treatment of dementia.展开更多
Amyloid-b,tau pathology,and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease(AD).However,these proteins represent only a fraction of the complex biological processes underlyi...Amyloid-b,tau pathology,and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease(AD).However,these proteins represent only a fraction of the complex biological processes underlying AD,and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers.More ADspecific early diagnostic and disease staging biomarkers are needed.In this study,we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid(CSF)and serum samples in a discovery cohort comprising 98 participants.Candidate biomarkers were validated by parallel reaction monitoring–based targeted proteomic assays in an independent multicenter cohort comprising 288 participants.We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort,identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers,respectively.In the validation cohort,58 and 21 CSF proteins,as well as 12 and 18 serum proteins,were verified as early diagnostic and staging biomarkers,respectively.Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment(MCI)due to AD from normal cognition with areas under the curve of 0.984 and 0.881,respectively.The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases.Moreover,we identified 21 CSF and 18 serum stage-associated proteins re-flecting AD stages.Our findings provide a foundation for developing bloodbased tests for AD screening and staging in clinical practice.展开更多
Audiovisual integration is a vital information process involved in cognition and is closely correlated with aging and Alzheimer’s disease(AD).In this review,we evaluated the altered audiovisual integrative behavioral...Audiovisual integration is a vital information process involved in cognition and is closely correlated with aging and Alzheimer’s disease(AD).In this review,we evaluated the altered audiovisual integrative behavioral symptoms in AD.We further analyzed the relationships between AD pathologies and audiovisual integration alterations bidirectionally and suggested the possible mechanisms of audiovisual integration alterations underlying AD,including the imbalance between energy demand and supply,activity-dependent degeneration,disrupted brain networks,and cognitive resource overloading.Then,based on the clinical characteristics including electrophysiological and imaging data related to audiovisual integration,we emphasized the value of audiovisual integration alterations as potential biomarkers for the early diagnosis and progression of AD.We also highlighted that treatments targeted audiovisual integration contributed to widespread pathological improvements in AD animal models and cognitive improvements in AD patients.Moreover,investigation into audiovisual integration alterations in AD also provided new insights and comprehension about sensory information processes.展开更多
Transgenic models are useful tools for studying the pathogenesis of and drug development for Alzheimer's Disease(AD).AD models are constructed usually using overexpression or knock-in of multiple pathogenic gene m...Transgenic models are useful tools for studying the pathogenesis of and drug development for Alzheimer's Disease(AD).AD models are constructed usually using overexpression or knock-in of multiple pathogenic gene mutations from familial AD.Each transgenic model has its unique behavioral and pathological features.This review summarizes the research progress of transgenic mouse models,and their progress in the unique mechanism of amyloid-βoligomers,including the first transgenic mouse model built in China based on a single gene mutation(PSEN1 V97L)found in Chinese familial AD.We further summarized the preclinical findings of drugs using the models,and their future application in exploring the upstream mechanisms and multi-target drug development in AD.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
Years of intensive research has brought us extensive knowledge on the genetic and molecular factors involved in Alzheimer's disease(AD).In addition to the mutations in the three main causative genes of familial AD...Years of intensive research has brought us extensive knowledge on the genetic and molecular factors involved in Alzheimer's disease(AD).In addition to the mutations in the three main causative genes of familial AD(FAD)including presenilins and amyloid precursor protein genes,studies have identified several genes as the most plausible genes for the onset and progression of FAD,such as triggering receptor expressed on myeloid cells 2,sortilin-related receptor 1,and adenosine triphosphate-binding cassette transporter subfamily A member 7.The apolipoprotein Eε4 allele is reported to be the strongest genetic risk factor for sporadic AD(SAD),and it also plays an important role in FAD.Here,we reviewed recent developments in genetic and molecular studies that contributed to the understanding of the genetic phenotypes of FAD and compared them with SAD.We further reviewed the advancements in AD gene therapy and discussed the future perspectives based on the genetic phenotypes.展开更多
Aging is an undeniable fact of life and the global population is aging to a historically unprecedented degree. The population aged65 years or older comprises 750 million people, representing nearly 10%of the global po...Aging is an undeniable fact of life and the global population is aging to a historically unprecedented degree. The population aged65 years or older comprises 750 million people, representing nearly 10%of the global population. As a result of prolonged life expectancy and falling mortality rates, China has become one of the most rapidly aging countries in the world, even surpassing several high-income countries in North America and Europe.展开更多
基金Capital’s Funds for Health Improvement and Re-search(CFH 2020-4-1033)。
文摘Neuroinflammation was linked to neu-rodegenerative diseases long ago,but no related treatment has proven effective.A new study unveils the inflammatory links between microglia and cognitive decline,providing new idea for the treatment of dementia.
基金This work was supported by grants from the Key Research and Development project of Zhejiang Province(2019C03039)the National Natural Science Foundation of China(81970998)+1 种基金the Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Projects(nos.2021ZD0201103 and 2021ZD0201803)the Integrative Traditional Chinese and Western Medicine Innovation Team for Neurodegenerative Diseases of Zhejiang Province.
文摘Amyloid-b,tau pathology,and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease(AD).However,these proteins represent only a fraction of the complex biological processes underlying AD,and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers.More ADspecific early diagnostic and disease staging biomarkers are needed.In this study,we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid(CSF)and serum samples in a discovery cohort comprising 98 participants.Candidate biomarkers were validated by parallel reaction monitoring–based targeted proteomic assays in an independent multicenter cohort comprising 288 participants.We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort,identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers,respectively.In the validation cohort,58 and 21 CSF proteins,as well as 12 and 18 serum proteins,were verified as early diagnostic and staging biomarkers,respectively.Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment(MCI)due to AD from normal cognition with areas under the curve of 0.984 and 0.881,respectively.The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases.Moreover,we identified 21 CSF and 18 serum stage-associated proteins re-flecting AD stages.Our findings provide a foundation for developing bloodbased tests for AD screening and staging in clinical practice.
基金supported by the National Key Research and Development Program of China(2022YFC3602600)National Natural Science Foundation of China(82220108009,81970996)STI2030-Major Projects(2021ZD0201801).
文摘Audiovisual integration is a vital information process involved in cognition and is closely correlated with aging and Alzheimer’s disease(AD).In this review,we evaluated the altered audiovisual integrative behavioral symptoms in AD.We further analyzed the relationships between AD pathologies and audiovisual integration alterations bidirectionally and suggested the possible mechanisms of audiovisual integration alterations underlying AD,including the imbalance between energy demand and supply,activity-dependent degeneration,disrupted brain networks,and cognitive resource overloading.Then,based on the clinical characteristics including electrophysiological and imaging data related to audiovisual integration,we emphasized the value of audiovisual integration alterations as potential biomarkers for the early diagnosis and progression of AD.We also highlighted that treatments targeted audiovisual integration contributed to widespread pathological improvements in AD animal models and cognitive improvements in AD patients.Moreover,investigation into audiovisual integration alterations in AD also provided new insights and comprehension about sensory information processes.
基金supported by the National Natural Science Foundation of China (U20A20354,81530036)Beijing Brain Initiative from Beijing Municipal Science&Technology Commission (Z201100005520016,Z201100005520017)+3 种基金the National Major R&D Projects of China-Scientific Technological Innovation 2030 (2021ZD0201802)the National Key Scientific Instrument and Equipment Development Project (31627803)Youth Program of National Natural Science Foundation of China (81801048,82101503)Youth Elite Scientists Sponsorship Program by CAST (YESS20200155)。
文摘Transgenic models are useful tools for studying the pathogenesis of and drug development for Alzheimer's Disease(AD).AD models are constructed usually using overexpression or knock-in of multiple pathogenic gene mutations from familial AD.Each transgenic model has its unique behavioral and pathological features.This review summarizes the research progress of transgenic mouse models,and their progress in the unique mechanism of amyloid-βoligomers,including the first transgenic mouse model built in China based on a single gene mutation(PSEN1 V97L)found in Chinese familial AD.We further summarized the preclinical findings of drugs using the models,and their future application in exploring the upstream mechanisms and multi-target drug development in AD.
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.
基金supported by the Key Project of the National Natural Science Foundation of China(U20A20354)Beijing Brain Initiative from Beijing Municipal Science&Technology Commission(Z201100005520016,Z201100005520017)+4 种基金National major R&D projects of China-Scientific technological innovation 2030(2021ZD0201802)the National Key Scientific Instrument and Equipment Development Project(31627803)the Key Project of the National Natural Science Foundation of China(81530036)Youth Program of National Natural Science Foundation of China(82101503)Beijing Postdoctoral Research Foundation.
文摘Years of intensive research has brought us extensive knowledge on the genetic and molecular factors involved in Alzheimer's disease(AD).In addition to the mutations in the three main causative genes of familial AD(FAD)including presenilins and amyloid precursor protein genes,studies have identified several genes as the most plausible genes for the onset and progression of FAD,such as triggering receptor expressed on myeloid cells 2,sortilin-related receptor 1,and adenosine triphosphate-binding cassette transporter subfamily A member 7.The apolipoprotein Eε4 allele is reported to be the strongest genetic risk factor for sporadic AD(SAD),and it also plays an important role in FAD.Here,we reviewed recent developments in genetic and molecular studies that contributed to the understanding of the genetic phenotypes of FAD and compared them with SAD.We further reviewed the advancements in AD gene therapy and discussed the future perspectives based on the genetic phenotypes.
基金supported by the Key Project of the National Natural Science Foundation of China(U20A20354)Beijing Brain Initiative from Beijing Municipal Science&Technology Commission(Z201100005520016 and Z201100005520017)+2 种基金National major R&D projects of China-Scientific technological innovation 2030(2021ZD0201802)the National Key Scientific Instrument and Equipment Development Project(31627803)the Key Project of the National Natural Science Foundation of China(81530036)。
文摘Aging is an undeniable fact of life and the global population is aging to a historically unprecedented degree. The population aged65 years or older comprises 750 million people, representing nearly 10%of the global population. As a result of prolonged life expectancy and falling mortality rates, China has become one of the most rapidly aging countries in the world, even surpassing several high-income countries in North America and Europe.