Background Alzheimer’s disease(AD)is a neurodegenerative disorder and the predominant type of dementia worldwide.It is characterized by the progressive and irreversible decline of cognitive functions.In addition to t...Background Alzheimer’s disease(AD)is a neurodegenerative disorder and the predominant type of dementia worldwide.It is characterized by the progressive and irreversible decline of cognitive functions.In addition to the pathological beta-amyloid(Aβ)deposition,glial activation,and neuronal injury in the postmortem brains of AD patients,increasing evidence suggests that the often overlooked vascular dysfunction is an important early event in AD pathophysiology.Vascular endothelial growth factor(VEGF)plays a critical role in regulating physiological functions and pathological changes in blood vessels,but whether VEGF is involved in the early stage of vascular pathology in AD remains unclear.Methods We used an antiangiogenic agent for clinical cancer treatment,the humanized monoclonal anti-VEGF antibody bevacizumab,to block VEGF binding to its receptors in the 5×FAD mouse model at an early age.After treatment,memory performance was evaluated by a novel object recognition test,and cerebral vascular permeability and perfusion were examined by an Evans blue assay and blood flow scanning imaging analysis.Immunofluorescence staining was used to measure glial activation and Aβdeposits.VEGF and its receptors were analyzed by enzyme-linked immunosorbent assay and immunoblotting.RNA sequencing was performed to elucidate bevacizumab-associated transcriptional signatures in the hippocampus of 5×FAD mice.Results Bevacizumab treatment administered from 4 months of age dramatically improved cerebrovascular functions,reduced glial activation,and restored long-term memory in both sexes of 5×FAD mice.Notably,a sex-specific change in different VEGF receptors was identified in the cortex and hippocampus of 5×FAD mice.Soluble VEGFR1 was decreased in female mice,while full-length VEGFR2 was increased in male mice.Bevacizumab treatment reversed the altered expression of receptors to be comparable to the level in the wild-type mice.Gene Set Enrichment Analysis of transcriptomic changes revealed that bevacizumab effectively reversed the changes in the gene sets associated with blood-brain barrier integrity and vascular smooth muscle contraction in 5×FAD mice.Conclusions Our study demonstrated the mechanistic roles of VEGF at the early stage of amyloidopathy and the protective effects of bevacizumab on cerebrovascular function and memory performance in 5×FAD mice.These findings also suggest the therapeutic potential of bevacizumab for the early intervention of AD.展开更多
We propose a versatile model with a flexible choice of control for an early-pandemic outbreak prevention when vaccine/drug is not yet available.At that stage,control is often limited to non-medical interventions like ...We propose a versatile model with a flexible choice of control for an early-pandemic outbreak prevention when vaccine/drug is not yet available.At that stage,control is often limited to non-medical interventions like social distancing and other behavioral changes.For the SIR optimal control problem,we show that the running cost of control satisfying mild,practically justified conditions generates an optimal strategy,u(t),t∈[0,T],that is sustainable up until some moment τ∈[0,T).However,for any t∈[τ,T],the function u(t)will decline as t approaches T,which may cause the number of newly infected people to increase.So,the window from 0 to τ is the time for public health officials to prepare alternative mitigation measures,such as vaccines,testing,antiviral medications,and others.In addition to theoretical study,we develop a fast and stable computational method for solving the proposed optimal control problem.The efficiency of the new method is illustrated with numerical examples of optimal control trajectories for various cost functions and weights.Simulation results provide a comprehensive demonstration of the effects of control on the epidemic spread and mitigation expenses,which can serve as invaluable references for public health officials.展开更多
基金supported by grants from the National Natural Science Foundation of China(81972967 to W.J.L.,32271068 to X.Y.,81925031 to Y.T.,81820108026 to Y.T.)Guangzhou Science and Technology Program key projects(202007030001 to Y.T.,X.Y.and W.J.L.),Guangdong Science。
文摘Background Alzheimer’s disease(AD)is a neurodegenerative disorder and the predominant type of dementia worldwide.It is characterized by the progressive and irreversible decline of cognitive functions.In addition to the pathological beta-amyloid(Aβ)deposition,glial activation,and neuronal injury in the postmortem brains of AD patients,increasing evidence suggests that the often overlooked vascular dysfunction is an important early event in AD pathophysiology.Vascular endothelial growth factor(VEGF)plays a critical role in regulating physiological functions and pathological changes in blood vessels,but whether VEGF is involved in the early stage of vascular pathology in AD remains unclear.Methods We used an antiangiogenic agent for clinical cancer treatment,the humanized monoclonal anti-VEGF antibody bevacizumab,to block VEGF binding to its receptors in the 5×FAD mouse model at an early age.After treatment,memory performance was evaluated by a novel object recognition test,and cerebral vascular permeability and perfusion were examined by an Evans blue assay and blood flow scanning imaging analysis.Immunofluorescence staining was used to measure glial activation and Aβdeposits.VEGF and its receptors were analyzed by enzyme-linked immunosorbent assay and immunoblotting.RNA sequencing was performed to elucidate bevacizumab-associated transcriptional signatures in the hippocampus of 5×FAD mice.Results Bevacizumab treatment administered from 4 months of age dramatically improved cerebrovascular functions,reduced glial activation,and restored long-term memory in both sexes of 5×FAD mice.Notably,a sex-specific change in different VEGF receptors was identified in the cortex and hippocampus of 5×FAD mice.Soluble VEGFR1 was decreased in female mice,while full-length VEGFR2 was increased in male mice.Bevacizumab treatment reversed the altered expression of receptors to be comparable to the level in the wild-type mice.Gene Set Enrichment Analysis of transcriptomic changes revealed that bevacizumab effectively reversed the changes in the gene sets associated with blood-brain barrier integrity and vascular smooth muscle contraction in 5×FAD mice.Conclusions Our study demonstrated the mechanistic roles of VEGF at the early stage of amyloidopathy and the protective effects of bevacizumab on cerebrovascular function and memory performance in 5×FAD mice.These findings also suggest the therapeutic potential of bevacizumab for the early intervention of AD.
基金Supported by NSF award 2011622(DMS Computational Mathematics)Supported by NSF award 2152960(DMS CDS&E)and 2307466(DMS Applied Mathematics).
文摘We propose a versatile model with a flexible choice of control for an early-pandemic outbreak prevention when vaccine/drug is not yet available.At that stage,control is often limited to non-medical interventions like social distancing and other behavioral changes.For the SIR optimal control problem,we show that the running cost of control satisfying mild,practically justified conditions generates an optimal strategy,u(t),t∈[0,T],that is sustainable up until some moment τ∈[0,T).However,for any t∈[τ,T],the function u(t)will decline as t approaches T,which may cause the number of newly infected people to increase.So,the window from 0 to τ is the time for public health officials to prepare alternative mitigation measures,such as vaccines,testing,antiviral medications,and others.In addition to theoretical study,we develop a fast and stable computational method for solving the proposed optimal control problem.The efficiency of the new method is illustrated with numerical examples of optimal control trajectories for various cost functions and weights.Simulation results provide a comprehensive demonstration of the effects of control on the epidemic spread and mitigation expenses,which can serve as invaluable references for public health officials.
