Background:The absence of effective animal models for sporadic Alzheimer's disease(AD)remains a pivotal barrier to therapy development.Because methanol metabolism produces endogenous formaldehyde,a neurotoxic agen...Background:The absence of effective animal models for sporadic Alzheimer's disease(AD)remains a pivotal barrier to therapy development.Because methanol metabolism produces endogenous formaldehyde,a neurotoxic agent linked to cognitive decline,this study investigated whether chronic,low-dose methanol exposure could recapitulate AD-like pathology and cognitive deficits in rhesus monkey,thereby establishing a nonhuman primate animal model driven by this environmental-metabolic insult.Methods:Adult rhesus monkeys received low-concentration methanol for 9 months.Behavioral tests for cognition,locomotion,sleep,and vision were conducted.Postmortem analyses involved histopathological examination,immunohistochemistry,immunofluorescence,and Western blot to evaluate neuronal integrity,microglial activation,and the expression of key proteins associated with AD(amyloid-β[Aβ],phosphorylated tau,TAR DNA-binding protein 43[TDP-43])and cellular stress(synaptic markers,mitochondrial fission,autophagy,and apoptosis-related proteins).Results:Chronic methanol exposure led to progressive cognitive and memory impairment without significant motor or visual deficits.Neuropathology revealed brain atrophy,neuronal loss,synaptic damage,microglial activation,and mitochondrial structural disorganization.Critically,the exposed animals exhibited hallmark AD-like molecular alterations,including increased Aβ deposition,tau hyperphosphorylation,and TDP-43 dysregulation.Furthermore,neurotoxicity was associated with elevated urinary formaldehyde,enhanced mitochondrial fission,increased autophagy,and elevated apoptosis.Conclusion:Chronic low-dose methanol exposure in rhesus monkeys recapitulates progressive cognitive deficits and AD-like neuropathological features.This model,driven by endogenous formaldehyde toxicity,effectively mimics key aspects of sporadic AD.Our findings shed light on the neurotoxic mechanisms of methanol and propose a reproducible and translationally relevant nonhuman primate model for studying AD pathogenesis and evaluating potential therapeutics.展开更多
Background:Hematopoietic stem cells(HSC)maintain the hematopoietic system homeostasis through self-renewal and multilineage differentiation potential.HSC are regulated by the microenvironment,cytokine signaling,and tr...Background:Hematopoietic stem cells(HSC)maintain the hematopoietic system homeostasis through self-renewal and multilineage differentiation potential.HSC are regulated by the microenvironment,cytokine signaling,and transcription factors.Recent results have shown that lipid pathways play a key role in the regulation of HSC quiescence,proliferation,and division.However,the mechanism by which lipid metabolism regulates HSC proliferation and differentiation remains to be clarified.Lipoprotein lipase(LPL)is an essential enzyme in the anabolism and catabolism of very low-density lipoprotein,chylomicrons,and triglyceride-rich lipoproteins.Methods:The percentage of hematopoietic stem/progenitor cells and immune cells were determined by fluorescence-activated cell sorting(FACS).The function and the mechanism of HSCs were analyzed by cell colony forming assay and qPCR analysis.The changes in LPL^(+/−)HSC microenvironment were detected by transplantation as-says using red fluorescent protein(RFP)transgenic mice.Results:To explore the function of LPL in HSC regulation,heterozygous LPL-knockout mice(LPL^(+/−))were established and analyzed by FACS.LPL^(+/−)mice displayed decreased hematopoietic stem/progenitor cell compartments.In vitro single-cell clono-genic assays and cell-cycle assays using FACS promoted the cell cycle and increased proliferation ability.qPCR analysis showed the expression of p57^(KIP2)and p21^(WAF1)/^(CIP1)in LPL^(+/−)mice was upregulated.Conclusions:LPL^(+/−)mice exhibited HSC compartment impairment due to promotion of HSC proliferation,without any effects on the bone marrow(BM)microenvironment.展开更多
Animal models provide an opportunity to assess the optimal treatment way and the underlying mechanisms of direct clinical application of adipose-derived stem cells(ADSCs).Previous studies have evaluated the effects of...Animal models provide an opportunity to assess the optimal treatment way and the underlying mechanisms of direct clinical application of adipose-derived stem cells(ADSCs).Previous studies have evaluated the effects of primitive and induced ADSCs in animal models of Parkinson’s disease(PD).Here,eight databases were systematically searched for studies on the effects and in vivo changes caused by ADSC intervention.Quality assessment was conducted using a 10-item risk of bias tool.For the subsequent meta-analysis,study characteristics were extracted and effect sizes were computed.Ten out of 2324 published articles(n=169 animals)were selected for further meta-analysis.After ADSC therapy,the rotation behavior(10 experiments,n=156 animals)and rotarod performance(3 experiments,n=54 animals)were improved(P<0.00001 and P=0.0003,respectively).The rotation behavior test reflected functional recovery,which may be due to the neurogenesis from neuronally differentiated ADSCs,resulting in a higher pooled effect size of standard mean difference(SMD)(−2.59;95%CI,−3.57 to−1.61)when compared to that of primitive cells(−2.18;95%CI,−3.29 to−1.07).Stratified analyses by different time intervals indicated that ADSC intervention exhibited a long-term effect.Following the transplantation of ADSCs,tyrosine hydroxylase-positive neurons recovered in the lesion area with pooled SMD of 13.36[6.85,19.86].Transplantation of ADSCs is a therapeutic option that shows long-lasting effects in animal models of PD.The potential mechanisms of ADSCs involve neurogenesis and neuroprotective effects.The standardized induction of neural form of transplanted ADSCs can lead to a future application in clinical practice.展开更多
基金Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-034Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2023-PT180-01+1 种基金PUMC Innovation Fund for Graduate Students,Grant/Award Number:2017-1001-07National Natural Science Foundation of China,Grant/Award Number:82161138027。
文摘Background:The absence of effective animal models for sporadic Alzheimer's disease(AD)remains a pivotal barrier to therapy development.Because methanol metabolism produces endogenous formaldehyde,a neurotoxic agent linked to cognitive decline,this study investigated whether chronic,low-dose methanol exposure could recapitulate AD-like pathology and cognitive deficits in rhesus monkey,thereby establishing a nonhuman primate animal model driven by this environmental-metabolic insult.Methods:Adult rhesus monkeys received low-concentration methanol for 9 months.Behavioral tests for cognition,locomotion,sleep,and vision were conducted.Postmortem analyses involved histopathological examination,immunohistochemistry,immunofluorescence,and Western blot to evaluate neuronal integrity,microglial activation,and the expression of key proteins associated with AD(amyloid-β[Aβ],phosphorylated tau,TAR DNA-binding protein 43[TDP-43])and cellular stress(synaptic markers,mitochondrial fission,autophagy,and apoptosis-related proteins).Results:Chronic methanol exposure led to progressive cognitive and memory impairment without significant motor or visual deficits.Neuropathology revealed brain atrophy,neuronal loss,synaptic damage,microglial activation,and mitochondrial structural disorganization.Critically,the exposed animals exhibited hallmark AD-like molecular alterations,including increased Aβ deposition,tau hyperphosphorylation,and TDP-43 dysregulation.Furthermore,neurotoxicity was associated with elevated urinary formaldehyde,enhanced mitochondrial fission,increased autophagy,and elevated apoptosis.Conclusion:Chronic low-dose methanol exposure in rhesus monkeys recapitulates progressive cognitive deficits and AD-like neuropathological features.This model,driven by endogenous formaldehyde toxicity,effectively mimics key aspects of sporadic AD.Our findings shed light on the neurotoxic mechanisms of methanol and propose a reproducible and translationally relevant nonhuman primate model for studying AD pathogenesis and evaluating potential therapeutics.
基金The Beijing Natural Science Foundation,Grant/Award Number:5202024The National Science Foundation of China,Grant/Award Number:31672374CAMS Innovation Fund for Medical Sciences(CIFMS),Grant/Award Number:2019-I2M-1-006.
文摘Background:Hematopoietic stem cells(HSC)maintain the hematopoietic system homeostasis through self-renewal and multilineage differentiation potential.HSC are regulated by the microenvironment,cytokine signaling,and transcription factors.Recent results have shown that lipid pathways play a key role in the regulation of HSC quiescence,proliferation,and division.However,the mechanism by which lipid metabolism regulates HSC proliferation and differentiation remains to be clarified.Lipoprotein lipase(LPL)is an essential enzyme in the anabolism and catabolism of very low-density lipoprotein,chylomicrons,and triglyceride-rich lipoproteins.Methods:The percentage of hematopoietic stem/progenitor cells and immune cells were determined by fluorescence-activated cell sorting(FACS).The function and the mechanism of HSCs were analyzed by cell colony forming assay and qPCR analysis.The changes in LPL^(+/−)HSC microenvironment were detected by transplantation as-says using red fluorescent protein(RFP)transgenic mice.Results:To explore the function of LPL in HSC regulation,heterozygous LPL-knockout mice(LPL^(+/−))were established and analyzed by FACS.LPL^(+/−)mice displayed decreased hematopoietic stem/progenitor cell compartments.In vitro single-cell clono-genic assays and cell-cycle assays using FACS promoted the cell cycle and increased proliferation ability.qPCR analysis showed the expression of p57^(KIP2)and p21^(WAF1)/^(CIP1)in LPL^(+/−)mice was upregulated.Conclusions:LPL^(+/−)mice exhibited HSC compartment impairment due to promotion of HSC proliferation,without any effects on the bone marrow(BM)microenvironment.
基金The authors acknowledge the financial support from the Research Fund for Doctor Innovation of Peking Union Medical College(2019-1001-14)Natural Science Foundation of Beijing Municipality(5171001)+1 种基金CAMS Innovation Fund for Medical Sciences(2019-I2M-1-006)Natural Science Foundation of Beijing Municipality(5202024).
文摘Animal models provide an opportunity to assess the optimal treatment way and the underlying mechanisms of direct clinical application of adipose-derived stem cells(ADSCs).Previous studies have evaluated the effects of primitive and induced ADSCs in animal models of Parkinson’s disease(PD).Here,eight databases were systematically searched for studies on the effects and in vivo changes caused by ADSC intervention.Quality assessment was conducted using a 10-item risk of bias tool.For the subsequent meta-analysis,study characteristics were extracted and effect sizes were computed.Ten out of 2324 published articles(n=169 animals)were selected for further meta-analysis.After ADSC therapy,the rotation behavior(10 experiments,n=156 animals)and rotarod performance(3 experiments,n=54 animals)were improved(P<0.00001 and P=0.0003,respectively).The rotation behavior test reflected functional recovery,which may be due to the neurogenesis from neuronally differentiated ADSCs,resulting in a higher pooled effect size of standard mean difference(SMD)(−2.59;95%CI,−3.57 to−1.61)when compared to that of primitive cells(−2.18;95%CI,−3.29 to−1.07).Stratified analyses by different time intervals indicated that ADSC intervention exhibited a long-term effect.Following the transplantation of ADSCs,tyrosine hydroxylase-positive neurons recovered in the lesion area with pooled SMD of 13.36[6.85,19.86].Transplantation of ADSCs is a therapeutic option that shows long-lasting effects in animal models of PD.The potential mechanisms of ADSCs involve neurogenesis and neuroprotective effects.The standardized induction of neural form of transplanted ADSCs can lead to a future application in clinical practice.
