Alzheimer's disease is a rather complex neurodegenerative disease,which is attributed to a combination of multiple factors.Among the many pathological pathways,synaptic dysfunctions,such as synapses loss and defic...Alzheimer's disease is a rather complex neurodegenerative disease,which is attributed to a combination of multiple factors.Among the many pathological pathways,synaptic dysfunctions,such as synapses loss and deficits in synaptic plasticity,were thought to be strongly associated with cognitive decline.The deficiencies in various sorts of neurotransmissions are responsible for the multifarious neurodegenerative symptoms in Alzheimer's disease,for example,the cholinergic and glutamatergic deficits for cognitive decline,the excitatory and inhibitory neurotransmission dyshomeostasis for synaptic plasticity deficits and epileptiform symptoms,and the monoamine neurotransmission for neuropsychiatric symptoms.Amyloid cascade hypothesis is the most popular pathological theory to explain Alzheimer's disease pathogenesis and attracts considerable attention.Multiple lines of genetic and pathological evidence support the predominant role of amyloid beta in Alzheimer's disease pathology.Neurofibrillary tangles assembled by microtubule-associated protein tau are other important histopathological characteristics in Alzheimer's disease brains.Cascade of tau toxicity was proved to lead to neuron damage,neuroinflammation and oxidative stress in brain.Ageing is the main risk factor of neurodegenerative diseases,and is associated with inflammation,oxidative stress,reduced metabolism,endocrine insufficiencies and organ failures.These aging related risk factors were also proved to be some of the risk factors contributing to Alzheimer's disease.In Alzheimer's disease drug development,many good therapeutic strategies have been investigated in clinical evaluations.However,complex mechanism of Alzheimer's disease and the interplay among different pathological factors call for the come out of allpowerful therapies with multiple curing functions.This review seeks to summarize some of the representative treatments targeting different pathological pathways currently under clinical evaluations.Multi-target therapies as an emerging strategy for Alzheimer's disease treatment will be highlighted.展开更多
Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative disorders.The GGGGCC·GG...Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative disorders.The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72(C9orf72)is the most genetic cause of both ALS and FTD.According to the previous studies,GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation,which produces dipeptide repeat(DPR)proteins.Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD,whether these DPRs can affect autophagy remains unclear.In the present study,we find that poly-GR and poly-PR,two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies,strongly inhibit starvation-induced autophagy.Moreover,our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation,therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells.Importantly,our study not only highlights the role of C9orf72 DPR in autophagy dysfunction,but also provides novel insight that pharmacological intervention of autophagy using SW063058,a small molecule compound that can disrupt the interaction between BECN1 and BCL2,may reduce C9orf72 DPR-induced neurotoxicity.展开更多
基金funded by University of Macao (File No.MYRG2016-00102-FHS)(to KYT)。
文摘Alzheimer's disease is a rather complex neurodegenerative disease,which is attributed to a combination of multiple factors.Among the many pathological pathways,synaptic dysfunctions,such as synapses loss and deficits in synaptic plasticity,were thought to be strongly associated with cognitive decline.The deficiencies in various sorts of neurotransmissions are responsible for the multifarious neurodegenerative symptoms in Alzheimer's disease,for example,the cholinergic and glutamatergic deficits for cognitive decline,the excitatory and inhibitory neurotransmission dyshomeostasis for synaptic plasticity deficits and epileptiform symptoms,and the monoamine neurotransmission for neuropsychiatric symptoms.Amyloid cascade hypothesis is the most popular pathological theory to explain Alzheimer's disease pathogenesis and attracts considerable attention.Multiple lines of genetic and pathological evidence support the predominant role of amyloid beta in Alzheimer's disease pathology.Neurofibrillary tangles assembled by microtubule-associated protein tau are other important histopathological characteristics in Alzheimer's disease brains.Cascade of tau toxicity was proved to lead to neuron damage,neuroinflammation and oxidative stress in brain.Ageing is the main risk factor of neurodegenerative diseases,and is associated with inflammation,oxidative stress,reduced metabolism,endocrine insufficiencies and organ failures.These aging related risk factors were also proved to be some of the risk factors contributing to Alzheimer's disease.In Alzheimer's disease drug development,many good therapeutic strategies have been investigated in clinical evaluations.However,complex mechanism of Alzheimer's disease and the interplay among different pathological factors call for the come out of allpowerful therapies with multiple curing functions.This review seeks to summarize some of the representative treatments targeting different pathological pathways currently under clinical evaluations.Multi-target therapies as an emerging strategy for Alzheimer's disease treatment will be highlighted.
基金This work was supported by the National Natural Science Foundation of China(Nos.82022022,32371018 and 82071274)a Project Funded by Jiangsu Key Laboratory of Neuropsychiatric Diseases(BM2013003,China)+4 种基金a Key Project of Natural Science Foundation of Jiangsu Provincial Higher Education Institutions(23KJA310005,China)a Project Funded by the Interdisciplinary Basic Frontier Innovation Program of Suzhou Medical College of Soochow University(MP13202823,China)a Project Funded by the Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases,and a Project Funded by the Priority Academic Program Development of the Jiangsu Higher Education Institutes(PAPD).J.H.M.P.was supported Science Foundation Ireland(17/COEN/3474,17/JPND/3455)Q.M.is a recipient of an RCSI International StAR Ph.D.scholarship.N.L.was supported by the Postgraduate Research&Practice Innovation Program of Jiangsu Province.K.Y.T.,was supported by the financial support from the Science and Technology Development Fund,Macao SAR(File no.0062/2021/A,China)University of Macao(File no.MYRG2022-00171-FHS,China).
文摘Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative disorders.The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72(C9orf72)is the most genetic cause of both ALS and FTD.According to the previous studies,GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation,which produces dipeptide repeat(DPR)proteins.Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD,whether these DPRs can affect autophagy remains unclear.In the present study,we find that poly-GR and poly-PR,two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies,strongly inhibit starvation-induced autophagy.Moreover,our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation,therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells.Importantly,our study not only highlights the role of C9orf72 DPR in autophagy dysfunction,but also provides novel insight that pharmacological intervention of autophagy using SW063058,a small molecule compound that can disrupt the interaction between BECN1 and BCL2,may reduce C9orf72 DPR-induced neurotoxicity.