Synapses are key structures involved in transmitting information in the nervous system,and their functions rely on the regulation of various lipids.Lipids play important roles in synapse formation,neurotransmitter rel...Synapses are key structures involved in transmitting information in the nervous system,and their functions rely on the regulation of various lipids.Lipids play important roles in synapse formation,neurotransmitter release,and signal transmission,and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases.The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention,but their specific mechanisms remain to be fully understood.This review aims to explore how lipids regulate synaptic activity in the central nervous system,focusing on their roles in synapse formation,neurotransmitter release,and signal transmission.Additionally,it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation.This review shows that within the central nervous system,lipids are essential components of the cell membrane bilayer,playing critical roles in synaptic structure and function.They regulate presynaptic vesicular trafficking,postsynaptic signaling pathways,and glial-neuronal interactions.Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts.Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles.Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis.Fatty acids are vital for energy metabolism and the synthesis of signaling molecules.Abnormalities in lipid metabolism may lead to impairments in synaptic function,affecting information transmission between neurons and the overall health of the nervous system.Therapeutic strategies targeting lipid metabolism,particularly through cholesterol modulation,show promise for treating these conditions.In neurodegenerative diseases such as Alzheimer’s disease,Parkinson disease,and amyotrophic lateral sclerosis,dysregulation of lipid metabolism is closely linked to synaptic dysfunction.Therefore,lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs.Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.展开更多
Alzheimer’s disease(AD)imposes a substantial clinical and societal burden,yet currently approved symptomatic therapies do not modify the underlying disease biology.Recently,three anti-amyloid monoclonal antibodies(ad...Alzheimer’s disease(AD)imposes a substantial clinical and societal burden,yet currently approved symptomatic therapies do not modify the underlying disease biology.Recently,three anti-amyloid monoclonal antibodies(aducanumab,lecanemab,and donanemab)have demonstrated robust amyloid clearance.Their clinical effects are statistically significant but modest,underscoring the need for broader,biologically informed strategies.Guided by the 2024 Alzheimer’s Association ATNIVS biomarker framework,this review synthesizes disease-modifying therapies(DMTs)targeting amyloid(A),tau(T),neurodegeneration(N),inflammation(I),vascular injury(V),andα-synuclein(S).For each domain,we summarize mechanisms of action and pivotal clinical trial results,highlighting safety considerations such as amyloid-related imaging abnormalities(ARIA)with anti-amyloid antibodies.We further outline future directions,including biomarker-based staging for trial enrollment,rational combination regimens(for example,anti-amyloid plus anti-tau),and endpoint selection aligned with minimal clinically important differences(MCID).Applying the ATNIVS framework to AD DMT development may accelerate the implementation of mechanism‑matched interventions.This approach can also facilitate precision therapeutics across diverse patient subgroups.展开更多
The field of therapy development for complex chronic brain disorders,which encompasses various forms of dementia including Alzheimer’s disease(AD),began to change dramatically during the last decade due to advances i...The field of therapy development for complex chronic brain disorders,which encompasses various forms of dementia including Alzheimer’s disease(AD),began to change dramatically during the last decade due to advances in knowledge about biology of the disease and technologies for detecting the progression of the condition.There is a growing consensus that the brain disorder commonly referred to as“Alzheimer disease”is not a single disease,but rather it is a cluster of syndromes.Therefore,a more accurate designation of the disorder is dementia-Alzheimer syndrome[1].Now,the options for interventions have expanded beyond short-term medication for symptomatic relief to include longer-lasting disease-modifying therapy(DMT).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
Background:Given the established genetic linkage between triggering receptors expressed on myeloid cells 2(TREM2)and Alzheimer’s disease(AD),an expanding research body has delved into the intricate role of TREM2 with...Background:Given the established genetic linkage between triggering receptors expressed on myeloid cells 2(TREM2)and Alzheimer’s disease(AD),an expanding research body has delved into the intricate role of TREM2 within the AD context.However,a conflicting landscape of outcomes has emerged from both in vivo and in vitro investigations.This study aimed to elucidate the multifaceted nuances and gain a clearer comprehension of the role of TREM2.Methods:PubMed database was searched spanning from its inception to January 2022.The search criteria took the form of("Alzheimer’s disease"OR"AD")AND("transgenic mice model"OR"transgenic mouse model")AND("Triggering receptor expressed on myeloid cells"OR"TREM2").Inclusion criteria consisted of the following:(1)publication of original studies in English;(2)utilization of transgenic mouse models for AD research;and(3)reports addressing the subject of TREM2.Results:A total of 43 eligible articles were identified.Our analysis addresses four pivotal queries concerning the interrelation of TREM2 with microglial function,Aβaccumulation,tau pathology,and inflammatory processes.However,the diverse inquiries posed yielded inconsistent responses.Nevertheless,the inconsistent roles of TREM2 within these AD mouse models potentially hinge upon factors such as age,sex,brain region,model type,and detection methodologies.Conclusions:This review substantiates the evolving understanding of TREM2’s disease progression-dependent impacts.Furthermore,it reviews the interplay between TREM2 and its effects across diverse tissues and temporal stages.展开更多
The effect of sleep on memory consolidation depends on the precise interaction of slow oscillations(SOs),theta bursts,and spindles.Disruption in coupling of these sleep rhythms has been reported for individuals with A...The effect of sleep on memory consolidation depends on the precise interaction of slow oscillations(SOs),theta bursts,and spindles.Disruption in coupling of these sleep rhythms has been reported for individuals with Alzheimer’s disease(AD).However,it is unknown how the sleep rhythms evolve during AD progression and whether disrupted sleep rhythms facilitate cognitive decline in AD.Here,we analyze data of 93 individuals from sleep electroencephalography(EEG),MRI,cerebrospinal fluid(CSF)AD biomarkers,and two-year cognitive assessments among three populations:AD dementia(n=33),mild cognitive impairment(MCI)due to AD(n=38),and cognitively normal(CN,n=22).Our study identifies the evolving pattern of coupled sleep rhythm disruption with advancing cognitive stages in AD.Specifically,the frequency of SO-theta burst coupling and SO-spindle coupling decreases from CN to MCI;SO-theta burst coupling and SO-spindle coupling further misalign from MCI to AD dementia.The APOEε4 allele and elevated amyloid and tau burden are associated with coupled sleep rhythm disruption.Hippocampal and medial prefrontal cortex atrophy are respectively linked to disruption of SO-theta burst coupling and SO-spindle coupling.Notably,coupled sleep rhythm disruption predicts accelerated cognitive decline over a two-year follow-up period.Our study presents that integrating sleep EEG with CSF and MRI biomarkers enhances the predictive ability for AD progression,which unravels the potential of sleep rhythms as monitoring and interventional targets for AD.展开更多
Temporal coding is known to be an integral aspect of multiple cognition and behavior,including language understanding,memory formation,and spatial navigation[1].This coding is supported by interactions between theta a...Temporal coding is known to be an integral aspect of multiple cognition and behavior,including language understanding,memory formation,and spatial navigation[1].This coding is supported by interactions between theta and gamma oscillations(thetagamma phase-amplitude coupling[PAC]),such that theta phase establishes a consistent reference for the formation of temporal associations among sequentially activated neuronal assemblies(firing in gamma oscillations)[2].展开更多
基金supported by the National Natural Science Foundation of China,No.82201568(to QQ)Capital’s Funds for Health Improvement and Research,No.2024-2-1031(to QQ)Beijing Nova Program,No.20240484566(to QQ).
文摘Synapses are key structures involved in transmitting information in the nervous system,and their functions rely on the regulation of various lipids.Lipids play important roles in synapse formation,neurotransmitter release,and signal transmission,and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases.The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention,but their specific mechanisms remain to be fully understood.This review aims to explore how lipids regulate synaptic activity in the central nervous system,focusing on their roles in synapse formation,neurotransmitter release,and signal transmission.Additionally,it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation.This review shows that within the central nervous system,lipids are essential components of the cell membrane bilayer,playing critical roles in synaptic structure and function.They regulate presynaptic vesicular trafficking,postsynaptic signaling pathways,and glial-neuronal interactions.Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts.Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles.Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis.Fatty acids are vital for energy metabolism and the synthesis of signaling molecules.Abnormalities in lipid metabolism may lead to impairments in synaptic function,affecting information transmission between neurons and the overall health of the nervous system.Therapeutic strategies targeting lipid metabolism,particularly through cholesterol modulation,show promise for treating these conditions.In neurodegenerative diseases such as Alzheimer’s disease,Parkinson disease,and amyotrophic lateral sclerosis,dysregulation of lipid metabolism is closely linked to synaptic dysfunction.Therefore,lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs.Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.
基金supported by the National Key Research and Development Program of China(2022YFC3602600)the National Natural Science Foundation of China(82220108009)+1 种基金Beijing Outstanding Young Scientist Program(JWZQ20240101023)STI2030-Major Projects(2021ZD0201801).
文摘Alzheimer’s disease(AD)imposes a substantial clinical and societal burden,yet currently approved symptomatic therapies do not modify the underlying disease biology.Recently,three anti-amyloid monoclonal antibodies(aducanumab,lecanemab,and donanemab)have demonstrated robust amyloid clearance.Their clinical effects are statistically significant but modest,underscoring the need for broader,biologically informed strategies.Guided by the 2024 Alzheimer’s Association ATNIVS biomarker framework,this review synthesizes disease-modifying therapies(DMTs)targeting amyloid(A),tau(T),neurodegeneration(N),inflammation(I),vascular injury(V),andα-synuclein(S).For each domain,we summarize mechanisms of action and pivotal clinical trial results,highlighting safety considerations such as amyloid-related imaging abnormalities(ARIA)with anti-amyloid antibodies.We further outline future directions,including biomarker-based staging for trial enrollment,rational combination regimens(for example,anti-amyloid plus anti-tau),and endpoint selection aligned with minimal clinically important differences(MCID).Applying the ATNIVS framework to AD DMT development may accelerate the implementation of mechanism‑matched interventions.This approach can also facilitate precision therapeutics across diverse patient subgroups.
基金supported by National Key Research and Development Program of China(2022YFC3602600)National Natural Science Foundation of China(82220108009)+1 种基金Beijing Outstanding Young Scientist Program(JWZQ20240101023)STI2030-Major Projects(2021ZD0201801).
文摘The field of therapy development for complex chronic brain disorders,which encompasses various forms of dementia including Alzheimer’s disease(AD),began to change dramatically during the last decade due to advances in knowledge about biology of the disease and technologies for detecting the progression of the condition.There is a growing consensus that the brain disorder commonly referred to as“Alzheimer disease”is not a single disease,but rather it is a cluster of syndromes.Therefore,a more accurate designation of the disorder is dementia-Alzheimer syndrome[1].Now,the options for interventions have expanded beyond short-term medication for symptomatic relief to include longer-lasting disease-modifying therapy(DMT).
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supported by grants from National Natural Science Foundation of China(Nos.82220108009,81970996,and 82201568)National Key Research and Development Program of China(No.2022YFC3602600)+3 种基金STI2030-Major Projects(No.2021ZD0201801)Young Elite Scientists Sponsorship Program by CAST(No.2021QNRC001)Beijing Hospitals Authority Innovation Studio of Young Staff Funding Support(No.202118)Beijing Nova Program(No.Z211100002121051).
文摘Background:Given the established genetic linkage between triggering receptors expressed on myeloid cells 2(TREM2)and Alzheimer’s disease(AD),an expanding research body has delved into the intricate role of TREM2 within the AD context.However,a conflicting landscape of outcomes has emerged from both in vivo and in vitro investigations.This study aimed to elucidate the multifaceted nuances and gain a clearer comprehension of the role of TREM2.Methods:PubMed database was searched spanning from its inception to January 2022.The search criteria took the form of("Alzheimer’s disease"OR"AD")AND("transgenic mice model"OR"transgenic mouse model")AND("Triggering receptor expressed on myeloid cells"OR"TREM2").Inclusion criteria consisted of the following:(1)publication of original studies in English;(2)utilization of transgenic mouse models for AD research;and(3)reports addressing the subject of TREM2.Results:A total of 43 eligible articles were identified.Our analysis addresses four pivotal queries concerning the interrelation of TREM2 with microglial function,Aβaccumulation,tau pathology,and inflammatory processes.However,the diverse inquiries posed yielded inconsistent responses.Nevertheless,the inconsistent roles of TREM2 within these AD mouse models potentially hinge upon factors such as age,sex,brain region,model type,and detection methodologies.Conclusions:This review substantiates the evolving understanding of TREM2’s disease progression-dependent impacts.Furthermore,it reviews the interplay between TREM2 and its effects across diverse tissues and temporal stages.
基金supported by the National Key Research and Development Program of China(2022YFC3602600 and 2023YFC3603200)the National Natural Science Foundation of China(82220108009,32271093,and 82401664)+2 种基金Beijing Outstanding Young Scientist Program(JWZQ20240101023)STI2030-Major Projects(2021ZD0201801)Beijing Hospitals Authority Youth Programme(QML20230802)。
文摘The effect of sleep on memory consolidation depends on the precise interaction of slow oscillations(SOs),theta bursts,and spindles.Disruption in coupling of these sleep rhythms has been reported for individuals with Alzheimer’s disease(AD).However,it is unknown how the sleep rhythms evolve during AD progression and whether disrupted sleep rhythms facilitate cognitive decline in AD.Here,we analyze data of 93 individuals from sleep electroencephalography(EEG),MRI,cerebrospinal fluid(CSF)AD biomarkers,and two-year cognitive assessments among three populations:AD dementia(n=33),mild cognitive impairment(MCI)due to AD(n=38),and cognitively normal(CN,n=22).Our study identifies the evolving pattern of coupled sleep rhythm disruption with advancing cognitive stages in AD.Specifically,the frequency of SO-theta burst coupling and SO-spindle coupling decreases from CN to MCI;SO-theta burst coupling and SO-spindle coupling further misalign from MCI to AD dementia.The APOEε4 allele and elevated amyloid and tau burden are associated with coupled sleep rhythm disruption.Hippocampal and medial prefrontal cortex atrophy are respectively linked to disruption of SO-theta burst coupling and SO-spindle coupling.Notably,coupled sleep rhythm disruption predicts accelerated cognitive decline over a two-year follow-up period.Our study presents that integrating sleep EEG with CSF and MRI biomarkers enhances the predictive ability for AD progression,which unravels the potential of sleep rhythms as monitoring and interventional targets for AD.
基金supported by the National Key Research and Development Program of China(2022YFC3602600)the National Natural Science Foundation of China(82220108009,82401664,and 62271331)+2 种基金the Beijing Outstanding Young Scientist Program(JWZQ20240101023)the STI2030-Major Projects(2021ZD0201801)the Beijing Hospitals Authority Youth Programme(QML20230802).
文摘Temporal coding is known to be an integral aspect of multiple cognition and behavior,including language understanding,memory formation,and spatial navigation[1].This coding is supported by interactions between theta and gamma oscillations(thetagamma phase-amplitude coupling[PAC]),such that theta phase establishes a consistent reference for the formation of temporal associations among sequentially activated neuronal assemblies(firing in gamma oscillations)[2].
