Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofib...Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles.Most of the Alzheimer’s drugs targeting amyloidβhave been failed in clinical trials.Particularly,tau pathology connects greatly in the pathogenesis of Alzheimer’s disease.Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron.Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved.The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state.Therefore,aberrant phosphorylation,as well as truncation of tau protein,has come into focus as significant mechanisms that make tau protein in a pathological entity.Furthermore,the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely.In this review,we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease.展开更多
Progressive aggregation of tau protein in neurons is associated with neurodegeneration in tauopathies.Cell non-autonomous disease mechanisms in astrocytes may be important drivers of the disease process but remain lar...Progressive aggregation of tau protein in neurons is associated with neurodegeneration in tauopathies.Cell non-autonomous disease mechanisms in astrocytes may be important drivers of the disease process but remain largely elusive.Here,we studied cell type-specific responses to intraneuronal tau aggregation prior to neurodegeneration.To this end,we developed a fully human co-culture model of seed-independent intraneuronal tau pathology,which shows no neuron and synapse loss.Using high-content microscopy,we show that intraneuronal tau aggregation induces oxidative stress accompanied by activation of the integrated stress response specifically in astrocytes.This requires the direct co-culture with neurons and is not related to neurodegeneration or extracellular tau levels.Tau-directed antisense therapy reduced intraneuronal tau levels and aggregation and prevented the cell non-autonomous responses in astrocytes.These data identify the astrocytic integrated stress response as a novel disease mechanism activated by intraneuronal tau aggregation.In addition,our data provide the first evidence for the efficacy of tau-directed antisense therapy to target cell autonomous and cell non-autonomous disease pathways in a fully human model of tau pathology.展开更多
Alzheimer's disease is characterized by two major neuropathological hallmarks—the extracellularβ-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau pro...Alzheimer's disease is characterized by two major neuropathological hallmarks—the extracellularβ-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau protein.Recent studies suggest that dysregulation of the microtubuleassociated protein Tau,especially specific proteolysis,could be a driving force for Alzheimer's disease neurodegeneration.Tau physiologically promotes the assembly and stabilization of microtubules,whereas specific truncated fragments are sufficient to induce abnormal hyperphosphorylation and aggregate into toxic oligomers,resulting in them gaining prion-like characteristics.In addition,Tau truncations cause extensive impairments to neural and glial cell functions and animal cognition and behavior in a fragment-dependent manner.This review summarizes over 60 proteolytic cleavage sites and their corresponding truncated fragments,investigates the role of specific truncations in physiological and pathological states of Alzheimer's disease,and summarizes the latest applications of strategies targeting Tau fragments in the diagnosis and treatment of Alzheimer's disease.展开更多
Synaptic vesicle transport by motor proteins along microtubules is a crucially active process underlying neuronal communication.It is known that microtubules are destabilized by tau-hyperphosphorylation,which causes t...Synaptic vesicle transport by motor proteins along microtubules is a crucially active process underlying neuronal communication.It is known that microtubules are destabilized by tau-hyperphosphorylation,which causes tau proteins to detach from microtubules and form neurofibril tangles.However,how tauphosphorylation affects the transport dynamics of motor proteins on the microtubule remains unknown.Here,we discover that the long-distance unidirectional motion of vesicle-motor protein multiplexes(VMPMs)in living cells is suppressed under tauhyperphosphorylation,with the consequent loss of fast vesicletransport along the microtubule.The VMPMs in hyperphosphorylated cells exhibit seemingly bidirectional random motion,with dynamic properties far different from those of VMPM motion in normal cells.We establish a parsimonious physicochemical model of VMPM’s active motion that provides a unified,quantitative explanation and predictions for our experimental results.Our analysis reveals that,under hyperphosphorylation conditions,motor protein multiplexes have both static and dynamic motility fluctuations.The loss of fast vesicle-transport along the microtubule can be a mechanism of neurodegenerative disorders associated with tau-hyperphosphorylation.展开更多
基金the support by the Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
文摘Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles.Most of the Alzheimer’s drugs targeting amyloidβhave been failed in clinical trials.Particularly,tau pathology connects greatly in the pathogenesis of Alzheimer’s disease.Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron.Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved.The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state.Therefore,aberrant phosphorylation,as well as truncation of tau protein,has come into focus as significant mechanisms that make tau protein in a pathological entity.Furthermore,the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely.In this review,we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease.
基金supported by ZonMW and Stichting Proefdiervrij(MKMD#114022506 to W.S.)co-funded by the PPP Allowance made available by Health~Holland,Top Sector Life Sciences&Health,to stimulate public-private partnerships(#LSHM17014 to V.M.H.and LSHM18024 to W.S.).
文摘Progressive aggregation of tau protein in neurons is associated with neurodegeneration in tauopathies.Cell non-autonomous disease mechanisms in astrocytes may be important drivers of the disease process but remain largely elusive.Here,we studied cell type-specific responses to intraneuronal tau aggregation prior to neurodegeneration.To this end,we developed a fully human co-culture model of seed-independent intraneuronal tau pathology,which shows no neuron and synapse loss.Using high-content microscopy,we show that intraneuronal tau aggregation induces oxidative stress accompanied by activation of the integrated stress response specifically in astrocytes.This requires the direct co-culture with neurons and is not related to neurodegeneration or extracellular tau levels.Tau-directed antisense therapy reduced intraneuronal tau levels and aggregation and prevented the cell non-autonomous responses in astrocytes.These data identify the astrocytic integrated stress response as a novel disease mechanism activated by intraneuronal tau aggregation.In addition,our data provide the first evidence for the efficacy of tau-directed antisense therapy to target cell autonomous and cell non-autonomous disease pathways in a fully human model of tau pathology.
基金supported by the Neural Regeneration Co-innovation Center of Jiangsu Province,Nantong University(to DC)the National Natural Science Foundation of China,Nos.81872853(to DC),81870941(to JHG)the Science and Technology Project of Nantong City,Nos.JC22022022(to FW)and JC2021059(to JM)。
文摘Alzheimer's disease is characterized by two major neuropathological hallmarks—the extracellularβ-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau protein.Recent studies suggest that dysregulation of the microtubuleassociated protein Tau,especially specific proteolysis,could be a driving force for Alzheimer's disease neurodegeneration.Tau physiologically promotes the assembly and stabilization of microtubules,whereas specific truncated fragments are sufficient to induce abnormal hyperphosphorylation and aggregate into toxic oligomers,resulting in them gaining prion-like characteristics.In addition,Tau truncations cause extensive impairments to neural and glial cell functions and animal cognition and behavior in a fragment-dependent manner.This review summarizes over 60 proteolytic cleavage sites and their corresponding truncated fragments,investigates the role of specific truncations in physiological and pathological states of Alzheimer's disease,and summarizes the latest applications of strategies targeting Tau fragments in the diagnosis and treatment of Alzheimer's disease.
基金supported by the grant awarded from GIST in 2020 through the Research Institute(GRI)program and by the National Research Foundation(NRF)of S.Korea(Grant no.2020R1F1A1073442,2021R1A2C2010557)J.S.was supported by the Creative Research Initiative Project Program(NRF-2015R1A3A2066497)+3 种基金the Engineering Research Center Program funded by the Korea government(MSIT)(NRF-2020R1A5A1018052)Y.H.S.,J.-H.K.,and M.H.L.were supported by the NRF[NRF-2019R1I1A1A01056975(Y.H.S.)NRF-2020R1A2C1102788(J.-H.K.)NRF-2022R1A3B1077319(M.H.L.)]。
文摘Synaptic vesicle transport by motor proteins along microtubules is a crucially active process underlying neuronal communication.It is known that microtubules are destabilized by tau-hyperphosphorylation,which causes tau proteins to detach from microtubules and form neurofibril tangles.However,how tauphosphorylation affects the transport dynamics of motor proteins on the microtubule remains unknown.Here,we discover that the long-distance unidirectional motion of vesicle-motor protein multiplexes(VMPMs)in living cells is suppressed under tauhyperphosphorylation,with the consequent loss of fast vesicletransport along the microtubule.The VMPMs in hyperphosphorylated cells exhibit seemingly bidirectional random motion,with dynamic properties far different from those of VMPM motion in normal cells.We establish a parsimonious physicochemical model of VMPM’s active motion that provides a unified,quantitative explanation and predictions for our experimental results.Our analysis reveals that,under hyperphosphorylation conditions,motor protein multiplexes have both static and dynamic motility fluctuations.The loss of fast vesicle-transport along the microtubule can be a mechanism of neurodegenerative disorders associated with tau-hyperphosphorylation.
