Alzheimer’s disease is a multi-amyloidosis disease characterized by amyloid-βdeposits in brain blood vessels,microaneurysms,and senile plaques.How amyloid-βdeposition affects axon pathology has not been examined ex...Alzheimer’s disease is a multi-amyloidosis disease characterized by amyloid-βdeposits in brain blood vessels,microaneurysms,and senile plaques.How amyloid-βdeposition affects axon pathology has not been examined extensively.We used immunohistochemistry and immunofluorescence staining to analyze the forebrain tissue slices of Alzheimer’s disease patients.Widespread axonal amyloidosis with distinctive axonal enlargement was observed in patients with Alzheimer’s disease.On average,amyloid-β-positive axon diameters in Alzheimer’s disease brains were 1.72 times those of control brain axons.Furthermore,axonal amyloidosis was associated with microtubule-associated protein 2 reduction,tau phosphorylation,lysosome destabilization,and several blood-related markers,such as apolipoprotein E,alpha-hemoglobin,glycosylated hemoglobin type A1C,and hemin.Lysosome destabilization in Alzheimer’s disease was also clearly identified in the neuronal soma,where it was associated with the co-expression of amyloid-β,Cathepsin D,alpha-hemoglobin,actin alpha 2,and collagen type IV.This suggests that exogenous hemorrhagic protein intake influences neural lysosome stability.Additionally,the data showed that amyloid-β-containing lysosomes were 2.23 times larger than control lysosomes.Furthermore,under rare conditions,axonal breakages were observed,which likely resulted in Wallerian degeneration.In summary,axonal enlargement associated with amyloidosis,micro-bleeding,and lysosome destabilization is a major defect in patients with Alzheimer’s disease.This finding suggests that,in addition to the well-documented neural soma and synaptic damage,axonal damage is a key component of neuronal defects in Alzheimer’s disease.展开更多
Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the...Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.展开更多
Adult hippocampal neurogenesis is linked to memory formation in the adult brain,with new neurons in the hippocampus exhibiting greater plasticity during their immature stages compared to mature neurons.Abnormal adult ...Adult hippocampal neurogenesis is linked to memory formation in the adult brain,with new neurons in the hippocampus exhibiting greater plasticity during their immature stages compared to mature neurons.Abnormal adult hippocampal neurogenesis is closely associated with cognitive impairment in central nervous system diseases.Targeting and regulating adult hippocampal neurogenesis have been shown to improve cognitive deficits.This review aims to expand the current understanding and prospects of targeting neurogenesis in the treatment of cognitive impairment.Recent research indicates the presence of abnormalities in AHN in several diseases associated with cognitive impairment,including cerebrovascular diseases,Alzheimer's disease,aging-related conditions,and issues related to anesthesia and surgery.The role of these abnormalities in the cognitive deficits caused by these diseases has been widely recognized,and targeting AHN is considered a promising approach for treating cognitive impairment.However,the underlying mechanisms of this role are not yet fully understood,and the effectiveness of targeting abnormal adult hippocampal neurogenesis for treatment remains limited,with a need for further development of treatment methods and detection techniques.By reviewing recent studies,we classify the potential mechanisms of adult hippocampal neurogenesis abnormalities into four categories:immunity,energy metabolism,aging,and pathological states.In immunity-related mechanisms,abnormalities in meningeal,brain,and peripheral immunity can disrupt normal adult hippocampal neurogenesis.Lipid metabolism and mitochondrial function disorders are significant energy metabolism factors that lead to abnormal adult hippocampal neurogenesis.During aging,the inflammatory state of the neurogenic niche and the expression of aging-related microRNAs contribute to reduced adult hippocampal neurogenesis and cognitive impairment in older adult patients.Pathological states of the body and emotional disorders may also result in abnormal adult hippocampal neurogenesis.Among the current strategies used to enhance this form of neurogenesis,physical therapies such as exercise,transcutaneous electrical nerve stimulation,and enriched environments have proven effective.Dietary interventions,including energy intake restriction and nutrient optimization,have shown efficacy in both basic research and clinical trials.However,drug treatments,such as antidepressants and stem cell therapy,are primarily reported in basic research,with limited clinical application.The relationship between abnormal adult hippocampal neurogenesis and cognitive impairment has garnered widespread attention,and targeting the former may be an important strategy for treating the latter.However,the mechanisms underlying abnormal adult hippocampal neurogenesis remain unclear,and treatments are lacking.This highlights the need for greater focus on translating research findings into clinical practice.展开更多
基金supported by the National Natural Science Foundation of China,No.81472235(to HF)the Shanghai Jiao Tong University Medical and Engineering Project,Nos.YG2021QN53(to HF),YG2017MS71(to HF)+1 种基金the International Cooperation Project of the National Natural Science Foundation of China,No.82020108017(to DC)the Innovation Group Project of the National Natural Science Foundation of China,No.81921002(to DC).
文摘Alzheimer’s disease is a multi-amyloidosis disease characterized by amyloid-βdeposits in brain blood vessels,microaneurysms,and senile plaques.How amyloid-βdeposition affects axon pathology has not been examined extensively.We used immunohistochemistry and immunofluorescence staining to analyze the forebrain tissue slices of Alzheimer’s disease patients.Widespread axonal amyloidosis with distinctive axonal enlargement was observed in patients with Alzheimer’s disease.On average,amyloid-β-positive axon diameters in Alzheimer’s disease brains were 1.72 times those of control brain axons.Furthermore,axonal amyloidosis was associated with microtubule-associated protein 2 reduction,tau phosphorylation,lysosome destabilization,and several blood-related markers,such as apolipoprotein E,alpha-hemoglobin,glycosylated hemoglobin type A1C,and hemin.Lysosome destabilization in Alzheimer’s disease was also clearly identified in the neuronal soma,where it was associated with the co-expression of amyloid-β,Cathepsin D,alpha-hemoglobin,actin alpha 2,and collagen type IV.This suggests that exogenous hemorrhagic protein intake influences neural lysosome stability.Additionally,the data showed that amyloid-β-containing lysosomes were 2.23 times larger than control lysosomes.Furthermore,under rare conditions,axonal breakages were observed,which likely resulted in Wallerian degeneration.In summary,axonal enlargement associated with amyloidosis,micro-bleeding,and lysosome destabilization is a major defect in patients with Alzheimer’s disease.This finding suggests that,in addition to the well-documented neural soma and synaptic damage,axonal damage is a key component of neuronal defects in Alzheimer’s disease.
基金supported by the Nature Science Foundation of Liaoning Province,Nos.2022-MS-211,2021-MS-064,and 2024-MS-048(all to YC).
文摘Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.
基金supported by Technological Innovation 2030-Major Projects of“Brain Science and Brain-like Research,”No.2022ZD0206200(to XG)the National Natural Science Foundation of China,No.82371245(to SJ),82102246(to XD),81701092(to XG)+2 种基金the Natural Science Foundation of Shandong Province,No.ZR2020MH129(to SJ)Shanghai Municipal Key Clinical Specialty,No.shslczdzk03601Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation,No.20DZ2254200。
文摘Adult hippocampal neurogenesis is linked to memory formation in the adult brain,with new neurons in the hippocampus exhibiting greater plasticity during their immature stages compared to mature neurons.Abnormal adult hippocampal neurogenesis is closely associated with cognitive impairment in central nervous system diseases.Targeting and regulating adult hippocampal neurogenesis have been shown to improve cognitive deficits.This review aims to expand the current understanding and prospects of targeting neurogenesis in the treatment of cognitive impairment.Recent research indicates the presence of abnormalities in AHN in several diseases associated with cognitive impairment,including cerebrovascular diseases,Alzheimer's disease,aging-related conditions,and issues related to anesthesia and surgery.The role of these abnormalities in the cognitive deficits caused by these diseases has been widely recognized,and targeting AHN is considered a promising approach for treating cognitive impairment.However,the underlying mechanisms of this role are not yet fully understood,and the effectiveness of targeting abnormal adult hippocampal neurogenesis for treatment remains limited,with a need for further development of treatment methods and detection techniques.By reviewing recent studies,we classify the potential mechanisms of adult hippocampal neurogenesis abnormalities into four categories:immunity,energy metabolism,aging,and pathological states.In immunity-related mechanisms,abnormalities in meningeal,brain,and peripheral immunity can disrupt normal adult hippocampal neurogenesis.Lipid metabolism and mitochondrial function disorders are significant energy metabolism factors that lead to abnormal adult hippocampal neurogenesis.During aging,the inflammatory state of the neurogenic niche and the expression of aging-related microRNAs contribute to reduced adult hippocampal neurogenesis and cognitive impairment in older adult patients.Pathological states of the body and emotional disorders may also result in abnormal adult hippocampal neurogenesis.Among the current strategies used to enhance this form of neurogenesis,physical therapies such as exercise,transcutaneous electrical nerve stimulation,and enriched environments have proven effective.Dietary interventions,including energy intake restriction and nutrient optimization,have shown efficacy in both basic research and clinical trials.However,drug treatments,such as antidepressants and stem cell therapy,are primarily reported in basic research,with limited clinical application.The relationship between abnormal adult hippocampal neurogenesis and cognitive impairment has garnered widespread attention,and targeting the former may be an important strategy for treating the latter.However,the mechanisms underlying abnormal adult hippocampal neurogenesis remain unclear,and treatments are lacking.This highlights the need for greater focus on translating research findings into clinical practice.
