Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has b...Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.展开更多
TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal...TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.展开更多
Atomic-scale doping strategies and structure design play pivotal roles in tailoring the electronic structure and physicochemical property of electromagnetic wave absorption(EMWA)materials.However,the relationship betw...Atomic-scale doping strategies and structure design play pivotal roles in tailoring the electronic structure and physicochemical property of electromagnetic wave absorption(EMWA)materials.However,the relationship between configuration and electromagnetic(EM)loss mechanism has remained elusive.Herein,drawing inspiration from the DNA transcription process,we report the successful synthesis of novel in situ Mn/N co-doped helical carbon nanotubes with ultrabroad EMWA capability.Theoretical calculation and EM simulation confirm that the orbital coupling and spin polarization of the Mn–N4–C configuration,along with cross polarization generated by the helical structure,endow the helical converters with enhanced EM loss.As a result,HMC-8 demonstrates outstanding EMWA performance,achieving a minimum reflection loss of−63.13 dB at an ultralow thickness of 1.29 mm.Through precise tuning of the graphite domain size,HMC-7 achieves an effective absorption bandwidth(EAB)of 6.08 GHz at 2.02 mm thickness.Furthermore,constructing macroscale gradient metamaterials enables an ultrabroadband EAB of 12.16 GHz at a thickness of only 5.00 mm,with the maximum radar cross section reduction value reaching 36.4 dB m2.This innovative approach not only advances the understanding of metal–nonmetal co-doping but also realizes broadband EMWA,thus contributing to the development of EMWA mechanisms and applications.展开更多
文摘Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.
基金supported by the Koeln Fortune Program/Faculty of Medicine,University of Cologne,the Alzheimer Forschung Initiative e.V.(grant#22039,to HZ)open-access funding from the DFG/GRC issued to the University of CologneAlzheimer Forschung Initiative e.V.for Open Access Publishing(a publication grant#P2401,to MAAK)。
文摘TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.
基金supported by the National Natural Science Foundation of China(22265021)the Aeronautical Science Foundation of China(2020Z056056003)Jiangxi Provincial Natural Science Foundation(20232BAB212004).
文摘Atomic-scale doping strategies and structure design play pivotal roles in tailoring the electronic structure and physicochemical property of electromagnetic wave absorption(EMWA)materials.However,the relationship between configuration and electromagnetic(EM)loss mechanism has remained elusive.Herein,drawing inspiration from the DNA transcription process,we report the successful synthesis of novel in situ Mn/N co-doped helical carbon nanotubes with ultrabroad EMWA capability.Theoretical calculation and EM simulation confirm that the orbital coupling and spin polarization of the Mn–N4–C configuration,along with cross polarization generated by the helical structure,endow the helical converters with enhanced EM loss.As a result,HMC-8 demonstrates outstanding EMWA performance,achieving a minimum reflection loss of−63.13 dB at an ultralow thickness of 1.29 mm.Through precise tuning of the graphite domain size,HMC-7 achieves an effective absorption bandwidth(EAB)of 6.08 GHz at 2.02 mm thickness.Furthermore,constructing macroscale gradient metamaterials enables an ultrabroadband EAB of 12.16 GHz at a thickness of only 5.00 mm,with the maximum radar cross section reduction value reaching 36.4 dB m2.This innovative approach not only advances the understanding of metal–nonmetal co-doping but also realizes broadband EMWA,thus contributing to the development of EMWA mechanisms and applications.
