The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cereb...The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cerebral organoids have emerged as valuable tools offering a more complex,versatile,and human-relevant system than traditional animal models,which are often unable to replicate the intricate architecture and functionality of the human brain.Since human cerebral organoids are a state-of-the-art model for the study of neurodevelopment and different pathologies affecting the brain,this field is currently under constant development,and work in this area is abundant.In this review,we give a complete overview of human cerebral organoids technology,starting from the different types of protocols that exist to generate different human cerebral organoids.We continue with the use of brain organoids for the study of brain pathologies,highlighting neurodevelopmental,psychiatric,neurodegenerative,brain tumor,and infectious diseases.Because of the potential value of human cerebral organoids,we describe their use in transplantation,drug screening,and toxicology assays.We also discuss the technologies available to study cell diversity and physiological characteristics of organoids.Finally,we summarize the limitations that currently exist in the field,such as the development of vasculature and microglia,and highlight some of the novel approaches being pursued through bioengineering.展开更多
The pathological implication of amyloid precursor protein(APP)in Alzheimer’s disease has been widely documented due to its involvement in the generation of amyloid-β peptide.However,the physiological functions of AP...The pathological implication of amyloid precursor protein(APP)in Alzheimer’s disease has been widely documented due to its involvement in the generation of amyloid-β peptide.However,the physiological functions of APP are still poorly understood.APP is considered a multimodal protein due to its role in a wide variety of processes,both in the embryo and in the adult brain.Specifically,APP seems to play a key role in the proliferation,differentiation and maturation of neural stem cells.In addition,APP can be processed through two canonical processing pathways,generating different functionally active fragments:soluble APP-α,soluble APP-β,amyloid-β peptide and the APP intracellular C-terminal domain.These fragments also appear to modulate various functions in neural stem cells,including the processes of proliferation,neurogenesis,gliogenesis or cell death.However,the molecular mechanisms involved in these effects are still unclear.In this review,we summarize the physiological functions of APP and its main proteolytic derivatives in neural stem cells,as well as the possible signaling pathways that could be implicated in these effects.The knowledge of these functions and signaling pathways involved in the onset or during the development of Alzheimer’s disease is essential to advance the understanding of the pathogenesis of Alzheimer’s disease,and in the search for potential therapeutic targets.展开更多
Although amyloid-βpeptide is considered neurotoxic,it may mediate several physiological processes during embryonic development and in the adult brain.The pathological function of amyloid-βpeptide has been extensivel...Although amyloid-βpeptide is considered neurotoxic,it may mediate several physiological processes during embryonic development and in the adult brain.The pathological function of amyloid-βpeptide has been extensively studied due to its implication in Alzheimer’s disease,but its physiological function remains poorly understood.Amyloid-βpeptide can be detected in non-aggregated(monomeric)and aggregated(oligomeric and fibrillary)forms.Each form has different cytotoxic and/or physiological properties,so amyloid-βpeptide and its role in Alzheimer’s disease need to be studied further.Neural stem cells and neural precursor cells are good tools for the study on neurodegenerative diseases and can provide future therapeutic applications in diseases such as Alzheimer’s disease.In this review,we provide an outline of the effects of amyloid-βpeptide,in monomeric and aggregated forms,on the biology of neural stem cells/neural precursor cells,and discuss the controversies.We also describe the possible molecular targets that could be implicated in these effects,especially GSK3β.A better understanding of amyloid-βpeptide(both physiological and pathological),and the signaling pathways involved are essential to advance the field of Alzheimer’s disease.展开更多
基金supported by the Grant PID2021-126715OB-IOO financed by MCIN/AEI/10.13039/501100011033 and"ERDFA way of making Europe"by the Grant PI22CⅢ/00055 funded by Instituto de Salud CarlosⅢ(ISCⅢ)+6 种基金the UFIECPY 398/19(PEJ2018-004965) grant to RGS funded by AEI(Spain)the UFIECPY-396/19(PEJ2018-004961)grant financed by MCIN (Spain)FI23CⅢ/00003 grant funded by ISCⅢ-PFIS Spain) to PMMthe UFIECPY 328/22 (PEJ-2021-TL/BMD-21001) grant to LM financed by CAM (Spain)the grant by CAPES (Coordination for the Improvement of Higher Education Personnel)through the PDSE program (Programa de Doutorado Sanduiche no Exterior)to VSCG financed by MEC (Brazil)
文摘The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cerebral organoids have emerged as valuable tools offering a more complex,versatile,and human-relevant system than traditional animal models,which are often unable to replicate the intricate architecture and functionality of the human brain.Since human cerebral organoids are a state-of-the-art model for the study of neurodevelopment and different pathologies affecting the brain,this field is currently under constant development,and work in this area is abundant.In this review,we give a complete overview of human cerebral organoids technology,starting from the different types of protocols that exist to generate different human cerebral organoids.We continue with the use of brain organoids for the study of brain pathologies,highlighting neurodevelopmental,psychiatric,neurodegenerative,brain tumor,and infectious diseases.Because of the potential value of human cerebral organoids,we describe their use in transplantation,drug screening,and toxicology assays.We also discuss the technologies available to study cell diversity and physiological characteristics of organoids.Finally,we summarize the limitations that currently exist in the field,such as the development of vasculature and microglia,and highlight some of the novel approaches being pursued through bioengineering.
基金supported by grants from the Ministerio de Ciencia e Innovación-Instituto de Salud Carlos Ⅲ(PI-10/00291 and MPY1412/09)Ministerio de Economía y Competitividad(SAF2015-71140-R)+2 种基金Comunidad de Madrid(Neurostem-Comunidad de Madrid consortium S2010/BMD-2336)supported by grants from Plan de Empleo Juvenil-Ministerio de Economía y Competitividad
文摘The pathological implication of amyloid precursor protein(APP)in Alzheimer’s disease has been widely documented due to its involvement in the generation of amyloid-β peptide.However,the physiological functions of APP are still poorly understood.APP is considered a multimodal protein due to its role in a wide variety of processes,both in the embryo and in the adult brain.Specifically,APP seems to play a key role in the proliferation,differentiation and maturation of neural stem cells.In addition,APP can be processed through two canonical processing pathways,generating different functionally active fragments:soluble APP-α,soluble APP-β,amyloid-β peptide and the APP intracellular C-terminal domain.These fragments also appear to modulate various functions in neural stem cells,including the processes of proliferation,neurogenesis,gliogenesis or cell death.However,the molecular mechanisms involved in these effects are still unclear.In this review,we summarize the physiological functions of APP and its main proteolytic derivatives in neural stem cells,as well as the possible signaling pathways that could be implicated in these effects.The knowledge of these functions and signaling pathways involved in the onset or during the development of Alzheimer’s disease is essential to advance the understanding of the pathogenesis of Alzheimer’s disease,and in the search for potential therapeutic targets.
基金supported by grants from the MICINN-ISCⅢ(PI-10/00291 and MPY1412/09)MINECO(SAF2015-71140-R)Comunidad de Madrid(NEUROSTEMCM consortium,S2010/BMD-2336)(all to IL)
文摘Although amyloid-βpeptide is considered neurotoxic,it may mediate several physiological processes during embryonic development and in the adult brain.The pathological function of amyloid-βpeptide has been extensively studied due to its implication in Alzheimer’s disease,but its physiological function remains poorly understood.Amyloid-βpeptide can be detected in non-aggregated(monomeric)and aggregated(oligomeric and fibrillary)forms.Each form has different cytotoxic and/or physiological properties,so amyloid-βpeptide and its role in Alzheimer’s disease need to be studied further.Neural stem cells and neural precursor cells are good tools for the study on neurodegenerative diseases and can provide future therapeutic applications in diseases such as Alzheimer’s disease.In this review,we provide an outline of the effects of amyloid-βpeptide,in monomeric and aggregated forms,on the biology of neural stem cells/neural precursor cells,and discuss the controversies.We also describe the possible molecular targets that could be implicated in these effects,especially GSK3β.A better understanding of amyloid-βpeptide(both physiological and pathological),and the signaling pathways involved are essential to advance the field of Alzheimer’s disease.
