Emerging evidence indicates that sleep deprivation(SD)can lead to Alzheimer’s disease(AD)-related pathological changes and cognitive decline.However,the underlying mechanisms remain obscure.In the present study,we id...Emerging evidence indicates that sleep deprivation(SD)can lead to Alzheimer’s disease(AD)-related pathological changes and cognitive decline.However,the underlying mechanisms remain obscure.In the present study,we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD.Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis,elevated NLRP3 inflammasome expression,GSK-3βactivation,autophagy dysfunction,and tau hyperphosphorylation in the hippocampus.Colonization with the“SD microbiota”replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice.Remarkably,both the deletion of NLRP3 in NLRP3-/-mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux,suppressed tau hyperphosphorylation,and ameliorated cognitive deficits induced by chronic SD,while GSK-3βactivity was not regulated by the NLRP3 inflammasome in chronic SD.Notably,deletion of NLRP3 reversed NLRP3 inflammasome activation,autophagy deficits,and tau hyperphosphorylation induced by GSK-3βactivation in primary hippocampal neurons,suggesting that GSK-3β,as a regulator of NLRP3-mediated autophagy dysfunction,plays a significant role in promoting tau hyperphosphorylation.Thus,gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction,ultimately leading to cognitive deficits.Overall,these findings highlight GSK-3βas a regulator of NLRP3-mediated autophagy dysfunction,playing a critical role in promoting tau hyperphosphorylation.展开更多
Sporadic or late-onset Alzheimer’s disease(LOAD)accounts for more than 95%of Alzheimer’s disease(AD)cases without any family history.Although genome-wide association studies have identified associated risk genes and...Sporadic or late-onset Alzheimer’s disease(LOAD)accounts for more than 95%of Alzheimer’s disease(AD)cases without any family history.Although genome-wide association studies have identified associated risk genes and loci for LOAD,numerous studies suggest that many adverse environmental factors,such as social isolation,are associated with an increased risk of dementia.However,the underlying mechanisms of social isolation in AD progression remain elusive.In the current study,we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice.We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus(DG)-enriched miRNAs,which simultaneously target reticulon 3(RTN3),an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons(MFBs)by recruiting multiple mitochondrial and vesicle-related proteins.Interestingly,the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation,which,in turn,further elevates RTN3 and forms a vicious cycle.Finally,using an artificial intelligence-assisted molecular docking approach,we determined that senktide,a selective agonist of neurokinin3 receptors(NK3R),could reduce the binding of RTN3 with its partners.Moreover,application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice.Taken together,our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.展开更多
Alzheimer’s disease(AD)is an age-related neurodegenerative disease with two major hallmarks:extracellular amyloid plaques made of amyloid-β(Aβ)and intracellular neurofibrillary tangles(NFTs)of abnormally hyperphosp...Alzheimer’s disease(AD)is an age-related neurodegenerative disease with two major hallmarks:extracellular amyloid plaques made of amyloid-β(Aβ)and intracellular neurofibrillary tangles(NFTs)of abnormally hyperphosphorylated tau.The number of NFTs correlates positively with the severity of dementia in AD patients.However,there is still no efficient therapy available for AD treatment and prevention so far.A deeper understanding of AD pathogenesis has identified novel strategies for the generation of specific therapies over the past few decades.Several studies have suggested that the prion-like seeding and spreading of tau pathology in the brain may be a key driver of AD.Tau protein is considered as a promising candidate target for the development of therapeutic interventions due to its considerable pathological role in a variety of neurodegenerative disorders.Abnormal tau hyperphosphorylation plays a detrimental pathological role,eventually leading to neurodegeneration.In the present review,we describe the recent research progresses in the pathological mechanisms of tau protein in AD and briefly discuss tau-based therapeutic strategies.展开更多
Alzheimer's disease(AD)is an age-related progressive neurodegenerative disorder that leads to cognitive impairment and memory loss.Emerging evidence suggests that autophagy plays an important role in the pathogene...Alzheimer's disease(AD)is an age-related progressive neurodegenerative disorder that leads to cognitive impairment and memory loss.Emerging evidence suggests that autophagy plays an important role in the pathogenesis of AD through the regulation of amyloid-beta(Aβ)and tau metabolism,and that autophagy dysfunction exacerbates amyloidosis and tau pathology.Therefore,targeting autophagy may be an effective approach for the treatment of AD.Animal models are considered useful tools for investigating the pathogenic mechanisms and therapeutic strategies of diseases.This review aims to summarize the pathological alterations in autophagy in representative AD animal models and to present recent studies on newly discovered autophagy-stimulating interventions in animal AD models.Finally,the opportunities,difficulties,and future directions of autophagy targeting in AD therapy are discussed.展开更多
Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or ...Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or autophagy dysregulation.This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders(tau pathology,synucleinopathy,polyglutamine tract,and motor neuron diseases).All animal studies on neurodegenerative diseases treated with trehalose published in Medline(accessed via EBSCOhost)and Scopus were considered.Of the 2259 studies screened,29 met the eligibility criteria.According to the SYstematic Review Center for Laboratory Animal Experiment(SYRCLE)risk of bias tool,we reported 22 out of 29 studies with a high risk of bias.The present findings support the purported role of trehalose in autophagic flux and protein refolding.This review identified several other lesser-known pathways,including modifying amyloid precursor protein processing,inhibition of reactive gliosis,the integrity of the blood-brain barrier,activation of growth factors,upregulation of the downstream antioxidant signaling pathway,and protection against mitochondrial defects.The absence of adverse events and improvements in the outcome parameters were observed in some studies,which supports the transition to human clinical trials.It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways.However,heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion.Translational studies on trehalose would need to clarify three important questions:1)bioavailability with oral administration,2)optimal time window to confer neuroprotective benefits,and 3)optimal dosage to confer neuroprotection.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
Alzheimer's disease(AD)is a neurodegenerative disease characterized by progressive cognitive decline,accompanied by amyloid-β(Aβ)overload and hyperphosphorylated tau accumulation in the brain.Synaptic dysfunctio...Alzheimer's disease(AD)is a neurodegenerative disease characterized by progressive cognitive decline,accompanied by amyloid-β(Aβ)overload and hyperphosphorylated tau accumulation in the brain.Synaptic dysfunction,an important pathological hallmark in AD;is recognized as the main cause of the cognitive impairments.Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD.Pathological tau,which is detached from axonal microtubules and mislocalized into pre-and postsynaptic neuronal compartments,is suggested to induce synaptic dysfunction in several ways,including reducing mobility and release of presynaptic vesicles,decreasing glutamatergic receptors,impairing the maturation of dendritic spines at postsynaptic terminals,disrupting mitochondrial transport and function in synapses,and promoting the phagocytosis of synapses by microglia.Here,we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD.We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.展开更多
Alzheimer’s disease(AD)is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors,accompanied by dysregulation of numerous intracellular signaling a...Alzheimer’s disease(AD)is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors,accompanied by dysregulation of numerous intracellular signaling and molecular pathways in the brain.At the cellular and molecular levels,the neuronal cellular milieu of the AD brain exhibits metabolic abnormalities,compromised bioenergetics,impaired lipid metabolism,and reduced overall metabolic capacity,which lead to abnormal neural network activity and impaired neuroplasticity,thus accelerating the formation of extracellular senile plaques and intracellular neurofibrillary tangles.The current absence of effective pharmacological therapies for AD points to the urgent need to investigate the benefits of non-pharmacological approaches such as physical exercise.Despite the evidence that regular physical activity can improve metabolic dysfunction in the AD state,inhibit different pathophysiological molecular pathways associated with AD,influence the pathological process of AD,and exert a protective effect,there is no clear consensus on the specific biological and molecular mechanisms underlying the advantages of physical exercise.Here,we review how physical exercise improves crucial molecular pathways and biological processes associated with metabolic disorders in AD,including glucose metabolism,lipid metabolism,Aβmetabolism and transport,iron metabolism and tau pathology.How metabolic states influence brain health is also presented.A better knowledge on the neurophysiological mechanisms by which exercise improves AD metabolism can contribute to the development of novel drugs and improvement of non-pharmacological interventions.展开更多
Idiopathic normal pressure hydrocephalus(iNPH)is a significant cause of the severe cognitive decline in the elderly population.There is no cure for iNPH,but cognitive symptoms can be partially alleviated through cereb...Idiopathic normal pressure hydrocephalus(iNPH)is a significant cause of the severe cognitive decline in the elderly population.There is no cure for iNPH,but cognitive symptoms can be partially alleviated through cerebrospinal fluid(CSF)diversion.In the early stages of iNPH,cognitive deficits occur primarily in the executive functions and working memory supported by frontostriatal circuits.As the disease progresses,cognition declines continuously and globally,leading to poor quality of life and daily functioning.In this review,we present recent advances in understanding the neurobiological mechanisms of cognitive impairment in iNPH,focusing on(1)abnormal CSF dynamics,(2)dysfunction of frontostriatal and entorhinal-hippocampal circuits and the default mode network,(3)abnormal neuromodulation,and(4)the presence of amyloid-βand tau pathologies.展开更多
基金National Natural Science Foundation of China(81870850)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX23_0322)。
文摘Emerging evidence indicates that sleep deprivation(SD)can lead to Alzheimer’s disease(AD)-related pathological changes and cognitive decline.However,the underlying mechanisms remain obscure.In the present study,we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD.Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis,elevated NLRP3 inflammasome expression,GSK-3βactivation,autophagy dysfunction,and tau hyperphosphorylation in the hippocampus.Colonization with the“SD microbiota”replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice.Remarkably,both the deletion of NLRP3 in NLRP3-/-mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux,suppressed tau hyperphosphorylation,and ameliorated cognitive deficits induced by chronic SD,while GSK-3βactivity was not regulated by the NLRP3 inflammasome in chronic SD.Notably,deletion of NLRP3 reversed NLRP3 inflammasome activation,autophagy deficits,and tau hyperphosphorylation induced by GSK-3βactivation in primary hippocampal neurons,suggesting that GSK-3β,as a regulator of NLRP3-mediated autophagy dysfunction,plays a significant role in promoting tau hyperphosphorylation.Thus,gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction,ultimately leading to cognitive deficits.Overall,these findings highlight GSK-3βas a regulator of NLRP3-mediated autophagy dysfunction,playing a critical role in promoting tau hyperphosphorylation.
基金supported partially by the National Key Research and Development Program of China(Grant Nos.2019YFE0121200,2022YFC2403905)the National Natural Science Foundation of China(Grant Nos.82325017,82371403,82030032,82261138555,31721002,32070960,82001164,82001256)+5 种基金Top-Notch Young Talents Program of China of 2014,the China Postdoctoral Science Foundation(Grant No.2018M642855)the Hubei Provincial Natural Science Foundation(Grant No.2022CFA004 to Dr.Ling-Qiang Zhu,2023AFA068 to Dr.Dan Liu,2020CFB657 to Dr.Kai Shu)University of South China Clinical Research 4310 Program(Grant No.20224310NHYCG08)the Science and Technology Innovation Program of Hunan Province(Grant No.2022RC4044)The Key R&D and Promotion Program of Henan Science and Technology Department(Grant Nos.182102310512,202102310354,222102310084)the Henan Province Medical Science and Technology Research Project(Grant No.SBGJ202103052).
文摘Sporadic or late-onset Alzheimer’s disease(LOAD)accounts for more than 95%of Alzheimer’s disease(AD)cases without any family history.Although genome-wide association studies have identified associated risk genes and loci for LOAD,numerous studies suggest that many adverse environmental factors,such as social isolation,are associated with an increased risk of dementia.However,the underlying mechanisms of social isolation in AD progression remain elusive.In the current study,we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice.We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus(DG)-enriched miRNAs,which simultaneously target reticulon 3(RTN3),an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons(MFBs)by recruiting multiple mitochondrial and vesicle-related proteins.Interestingly,the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation,which,in turn,further elevates RTN3 and forms a vicious cycle.Finally,using an artificial intelligence-assisted molecular docking approach,we determined that senktide,a selective agonist of neurokinin3 receptors(NK3R),could reduce the binding of RTN3 with its partners.Moreover,application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice.Taken together,our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.
基金This project was supported by National Natural Science Foundation of China(No.31870772).
文摘Alzheimer’s disease(AD)is an age-related neurodegenerative disease with two major hallmarks:extracellular amyloid plaques made of amyloid-β(Aβ)and intracellular neurofibrillary tangles(NFTs)of abnormally hyperphosphorylated tau.The number of NFTs correlates positively with the severity of dementia in AD patients.However,there is still no efficient therapy available for AD treatment and prevention so far.A deeper understanding of AD pathogenesis has identified novel strategies for the generation of specific therapies over the past few decades.Several studies have suggested that the prion-like seeding and spreading of tau pathology in the brain may be a key driver of AD.Tau protein is considered as a promising candidate target for the development of therapeutic interventions due to its considerable pathological role in a variety of neurodegenerative disorders.Abnormal tau hyperphosphorylation plays a detrimental pathological role,eventually leading to neurodegeneration.In the present review,we describe the recent research progresses in the pathological mechanisms of tau protein in AD and briefly discuss tau-based therapeutic strategies.
基金supported by the National Natural Science Foundation of China (82271455)Guangdong Basic and Applied Basic Research Foundation (2022A1515012416)+6 种基金Science and Technology Development FundMacao SAR (0128/2019/A3,0025/2022/A1)Shenzhen Fundamental Research Program (SGDX20210823103804030)University of Macao Grants (MYRG2022-00094-ICMS)awarded to J.H.L.partially supported by the National Key R&D Program of China (2021YFA0805901)National Natural Science Foundation of China (82070199)Guangdong Basic and Applied Basic Research Foundation (2021A1515220078)awarded to D.S.T。
文摘Alzheimer's disease(AD)is an age-related progressive neurodegenerative disorder that leads to cognitive impairment and memory loss.Emerging evidence suggests that autophagy plays an important role in the pathogenesis of AD through the regulation of amyloid-beta(Aβ)and tau metabolism,and that autophagy dysfunction exacerbates amyloidosis and tau pathology.Therefore,targeting autophagy may be an effective approach for the treatment of AD.Animal models are considered useful tools for investigating the pathogenic mechanisms and therapeutic strategies of diseases.This review aims to summarize the pathological alterations in autophagy in representative AD animal models and to present recent studies on newly discovered autophagy-stimulating interventions in animal AD models.Finally,the opportunities,difficulties,and future directions of autophagy targeting in AD therapy are discussed.
基金supported by Dana Impak Perdana Grant(DIP-2019-007)received by NMI from Universiti Kebangsaan Malaysia.
文摘Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or autophagy dysregulation.This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders(tau pathology,synucleinopathy,polyglutamine tract,and motor neuron diseases).All animal studies on neurodegenerative diseases treated with trehalose published in Medline(accessed via EBSCOhost)and Scopus were considered.Of the 2259 studies screened,29 met the eligibility criteria.According to the SYstematic Review Center for Laboratory Animal Experiment(SYRCLE)risk of bias tool,we reported 22 out of 29 studies with a high risk of bias.The present findings support the purported role of trehalose in autophagic flux and protein refolding.This review identified several other lesser-known pathways,including modifying amyloid precursor protein processing,inhibition of reactive gliosis,the integrity of the blood-brain barrier,activation of growth factors,upregulation of the downstream antioxidant signaling pathway,and protection against mitochondrial defects.The absence of adverse events and improvements in the outcome parameters were observed in some studies,which supports the transition to human clinical trials.It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways.However,heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion.Translational studies on trehalose would need to clarify three important questions:1)bioavailability with oral administration,2)optimal time window to confer neuroprotective benefits,and 3)optimal dosage to confer neuroprotection.
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 partially by the National Natural Science Foundation of China(82030032,32070960,81871108 to DL,81760221 and 81960221 to XPY,and 81660209 to ZYC)the National Science&Technology Fundamental Resource Investigation Program of China(2018FY100903 to XPY)Science and Technology Project Founded by the Education Department of Jiangxi Province(GJJ201834 to MXW).
文摘Alzheimer's disease(AD)is a neurodegenerative disease characterized by progressive cognitive decline,accompanied by amyloid-β(Aβ)overload and hyperphosphorylated tau accumulation in the brain.Synaptic dysfunction,an important pathological hallmark in AD;is recognized as the main cause of the cognitive impairments.Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD.Pathological tau,which is detached from axonal microtubules and mislocalized into pre-and postsynaptic neuronal compartments,is suggested to induce synaptic dysfunction in several ways,including reducing mobility and release of presynaptic vesicles,decreasing glutamatergic receptors,impairing the maturation of dendritic spines at postsynaptic terminals,disrupting mitochondrial transport and function in synapses,and promoting the phagocytosis of synapses by microglia.Here,we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD.We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.
文摘Alzheimer’s disease(AD)is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors,accompanied by dysregulation of numerous intracellular signaling and molecular pathways in the brain.At the cellular and molecular levels,the neuronal cellular milieu of the AD brain exhibits metabolic abnormalities,compromised bioenergetics,impaired lipid metabolism,and reduced overall metabolic capacity,which lead to abnormal neural network activity and impaired neuroplasticity,thus accelerating the formation of extracellular senile plaques and intracellular neurofibrillary tangles.The current absence of effective pharmacological therapies for AD points to the urgent need to investigate the benefits of non-pharmacological approaches such as physical exercise.Despite the evidence that regular physical activity can improve metabolic dysfunction in the AD state,inhibit different pathophysiological molecular pathways associated with AD,influence the pathological process of AD,and exert a protective effect,there is no clear consensus on the specific biological and molecular mechanisms underlying the advantages of physical exercise.Here,we review how physical exercise improves crucial molecular pathways and biological processes associated with metabolic disorders in AD,including glucose metabolism,lipid metabolism,Aβmetabolism and transport,iron metabolism and tau pathology.How metabolic states influence brain health is also presented.A better knowledge on the neurophysiological mechanisms by which exercise improves AD metabolism can contribute to the development of novel drugs and improvement of non-pharmacological interventions.
基金supported by the National Natural Science Foundation of China(31961133025).
文摘Idiopathic normal pressure hydrocephalus(iNPH)is a significant cause of the severe cognitive decline in the elderly population.There is no cure for iNPH,but cognitive symptoms can be partially alleviated through cerebrospinal fluid(CSF)diversion.In the early stages of iNPH,cognitive deficits occur primarily in the executive functions and working memory supported by frontostriatal circuits.As the disease progresses,cognition declines continuously and globally,leading to poor quality of life and daily functioning.In this review,we present recent advances in understanding the neurobiological mechanisms of cognitive impairment in iNPH,focusing on(1)abnormal CSF dynamics,(2)dysfunction of frontostriatal and entorhinal-hippocampal circuits and the default mode network,(3)abnormal neuromodulation,and(4)the presence of amyloid-βand tau pathologies.
