Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults.Pathogenic factors,such as oxidative stress,an increase in acetylcholinester...Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults.Pathogenic factors,such as oxidative stress,an increase in acetylcholinesterase activity,mitochondrial dysfunction,genotoxicity,and neuroinflammation are present in this syndrome,which leads to neurodegeneration.Neurodegenerative pathologies such as Alzheimer’s disease are considered late-onset diseases caused by the complex combination of genetic,epigenetic,and environmental factors.There are two main types of Alzheimer’s disease,known as familial Alzheimer’s disease(onset<65 years)and late-onset or sporadic Alzheimer’s disease(onset≥65 years).Patients with familial Alzheimer’s disease inherit the disease due to rare mutations on the amyloid precursor protein(APP),presenilin 1 and 2(PSEN1 and PSEN2)genes in an autosomaldominantly fashion with closely 100%penetrance.In contrast,a different picture seems to emerge for sporadic Alzheimer’s disease,which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology.Importantly,the fundamental pathophysiological mechanisms driving Alzheimer’s disease are interfaced with epigenetic dysregulation.However,the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer’s disease or following injury or stroke in humans.In recent years,there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer’s disease.Through epigenetic mechanisms,such as DNA methylation,non-coding RNAs,histone modification,and chromatin conformation regulation,natural compounds appear to exert neuroprotective effects.While we do not purport to cover every in this work,we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer’s disease-related genes.展开更多
Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport ...Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.展开更多
Highly specific interactions between biomolecules,such as antigen-antibody,protein-ligand,or nucleic acid base pair complementary are on the basis of the organization of complex organisms.The same principles may be te...Highly specific interactions between biomolecules,such as antigen-antibody,protein-ligand,or nucleic acid base pair complementary are on the basis of the organization of complex organisms.The same principles may be tentatively used in molecular medicine for diagnosis and therapeutics.A molecule can be designed to selectively bind a protease and thereby inhibit the production of a peptide that forms toxic aggregates in the brain or an antibody may be produced to bind specifically to that peptide for detection or clearance purposes.Unfortunately,interference in biological systems is not that simple.For a start there is the inhibition of the physiological role of the protease;moreover,several cleavage fragments may be produced,which may continue to diverge due to putative post-translational modification and self-assembly processes,hiding the toxic target in a“soup”of peptide species varying in size,structure and chemical composition.A perspective of the current status and challenges in targeting peptide species for diagnosis and treatment in the context of Alzheimer’s disease is given.展开更多
Recent progress in the treatment of Alzheimer’s disease(AD)using antibodies against amyloid sustains amyloid generation as a key process in AD.Amyloid formation starts with two amyloidbeta(Aβ)molecules interacting(d...Recent progress in the treatment of Alzheimer’s disease(AD)using antibodies against amyloid sustains amyloid generation as a key process in AD.Amyloid formation starts with two amyloidbeta(Aβ)molecules interacting(dimer formation)followed by an accelerating build-up of socalled protofibrils,which turn into fibrils,which accumulate in the characteristic plaques.展开更多
Neuronal necroptosis-an emerging form of regulated cell death associated with neuroinflammatory signaling:Alzheimer’s disease(AD)is characterized by the presence of extracellular amyloid-β(Aβ)plaques and intracellu...Neuronal necroptosis-an emerging form of regulated cell death associated with neuroinflammatory signaling:Alzheimer’s disease(AD)is characterized by the presence of extracellular amyloid-β(Aβ)plaques and intracellular tau neurofibrillary tangles as well as progressive neuronal loss.Recent evidence has suggested that prolonged neuroinflammation with increased levels of cytokines,arising from neuronal injury,innate immune responses from glial cells,and peripheral inflammation,leads to neuronal death and AD progression.展开更多
Alzheimer’s disease(AD),the most common type of dementia,affects millions of people worldwide,putting a significant strain on healthcare infrastructure and societal resources.AD is characte rized by the build-up of a...Alzheimer’s disease(AD),the most common type of dementia,affects millions of people worldwide,putting a significant strain on healthcare infrastructure and societal resources.AD is characte rized by the build-up of amyloid-beta(Aβ)plaques and neurofibrillary to ngles containing hyperphosphorylated tau protein.展开更多
Alzheimer's disease(AD)is the most frequent,form of dementia in elderly people and is an incurable disease with an exponentially growing number of cases.Extracellular deposition of amyloid-β(Aβ)plaques and intra...Alzheimer's disease(AD)is the most frequent,form of dementia in elderly people and is an incurable disease with an exponentially growing number of cases.Extracellular deposition of amyloid-β(Aβ)plaques and intraneuronal formation of neurofibrillary tangles represent neuropathological hallmarks of AD.展开更多
Alzheimer’s disease(AD)is the most prevalent form of dementia,i.e.,progressive memory loss and profound cognitive dysfunction,resulting in a considerable societal burden.At the neuropathological level,the brains of A...Alzheimer’s disease(AD)is the most prevalent form of dementia,i.e.,progressive memory loss and profound cognitive dysfunction,resulting in a considerable societal burden.At the neuropathological level,the brains of AD patients exhibit amyloid-β(Aβ)plaques,neurofibrillary tangles,and neuroinflammation(Sala Frigerio and De Strooper,2016).展开更多
Alzheimer's disease(AD) is a progressive neurodegenerative disease histologically characterized by the presence of extraneuronal plaques,mainly formed by the 42-aminoacid isoform of amyloid-(Aβ_(1-42)),and by int...Alzheimer's disease(AD) is a progressive neurodegenerative disease histologically characterized by the presence of extraneuronal plaques,mainly formed by the 42-aminoacid isoform of amyloid-(Aβ_(1-42)),and by intraneuronal neurofibrillary to ngles,mainly formed by the tau protein and its hyperphosphorylated isoforms(p-tau).AD is the most common cause of dementia,with an estimated lifetime risk of about 1 in 10 for men and 1 in 5 for women.展开更多
Brain vascular dysfunction in Alzheimer s disease(AD) pathogenesis has become increasingly clea r.Accumulating evidence shows that damaged vascular,including large or small vessels and even neurovascular unit,may acce...Brain vascular dysfunction in Alzheimer s disease(AD) pathogenesis has become increasingly clea r.Accumulating evidence shows that damaged vascular,including large or small vessels and even neurovascular unit,may accelerate the neuropathological process of AD via disrupting brain hypoperfusion,aberrant angiogenesis,and neuroinflammatory response,etc.Thus,vascular dysfunction makes a substantially contribution to the cognitive decline of AD patients.展开更多
Over 55 million people globally live with Alzheimer’s disease(AD)or related dementias(ADRD)and the number is expected to double every twenty years.Unt i l recent l y,onl y symptomatic treatments were available to pat...Over 55 million people globally live with Alzheimer’s disease(AD)or related dementias(ADRD)and the number is expected to double every twenty years.Unt i l recent l y,onl y symptomatic treatments were available to patients with AD,including acetylcholine esterase inhibitors,of which the last one,galantamine,was approved by the US Food and Drug Administration(FDA)in 2001.展开更多
Loneliness is classically defined as a result of perceiving a discrepancy between the desired quantity and quality of one's social life and actual social relationships(Perlman and Peplau,1984).Lifespan research ha...Loneliness is classically defined as a result of perceiving a discrepancy between the desired quantity and quality of one's social life and actual social relationships(Perlman and Peplau,1984).Lifespan research has indicated older adults are among the highest risk for experiencing loneliness because their social network size decreases more frequently than that of younger adults.展开更多
Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and society.Neuropathological hallmarks of AD,evi...Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and society.Neuropathological hallmarks of AD,evident in postmortem AD brains,include a massive loss of the grey matter in the neocortex,extracellular deposition of amyloid-β(Aβ)in the form of senile plaques and cerebrovascular amyloid angiopathy,and intra-neuronal accumulation of neurofibrillary tangles,formed by hyper-phosphorylated tau protein.展开更多
The critical role of calcium dyshomeostasis in the pathogenesis of Alzheimer’s disease(AD):AD is a progressive neurodegenerative disease characterized by cognitive decline,memory impairment,and behavioral changes.Wit...The critical role of calcium dyshomeostasis in the pathogenesis of Alzheimer’s disease(AD):AD is a progressive neurodegenerative disease characterized by cognitive decline,memory impairment,and behavioral changes.With an estimated 50 million people being affected worldwide,the incidence of AD is constantly increasing globally.The hallmark of AD is the accumulation of amyloid-beta protein(Aβ)in the form of amyloid plaques and hyperphosphorylated tau protein in the form of neurofibrillary tangles.However,increasing evidence suggests that calcium ion(Ca2+)dysregulation also plays a crucial role in the pathogenesis of AD(Calvo-Rodriguez and Bacskai,2021).As a key second messenger,Ca2+regulates a wide range of cellular processes,including the release of neurotransmitters,gene expression,and cell death.Ca^(2+)also regulates the activity of Calcium/calmodulin-dependent protein kinase II,which is critical for synaptic plasticity,learning,and memory(Kaushik et al.,2022).Alternation in the Ca^(2+)signal is an early event in the pathogenesis of AD,which can lead to synaptic dysfunction,neuronal loss,and cognitive impairment.展开更多
Dementia is a devastating syndrome characterized by memory problems,confusion,and behavior changes that prevent people from performing everyday activities.It is the leading cause of dependency and disability amongst o...Dementia is a devastating syndrome characterized by memory problems,confusion,and behavior changes that prevent people from performing everyday activities.It is the leading cause of dependency and disability amongst older people,resulting in a global economic cost of ~$1.3 trillion.Around 58 million people are currently afflicted by dementia worldwide,with Alzheimer s disease(AD) causing most(60-70%) of these cases.展开更多
While extensive studies have illuminated the impact of Alzheimer's disease(AD) on neuronal survival,there is growing evidence that abnormal postnatal neurogenesis in early AD brains contributes to disease progress...While extensive studies have illuminated the impact of Alzheimer's disease(AD) on neuronal survival,there is growing evidence that abnormal postnatal neurogenesis in early AD brains contributes to disease progression.Postnatal neurogenesis serves as a mechanism to replace dead or damaged neurons.New neurons generated from neural stem cells(NSCs) in the subgranular zone(SGZ) of the dentate gyrus integrate into the existing hippocampal circuit.展开更多
Due to increasing life expectancy,the amount of people with dementia worldwide is expected to experience a substantial rise,with estimates indicating a growth from 55 million in 2019 to a staggering 139 million by the...Due to increasing life expectancy,the amount of people with dementia worldwide is expected to experience a substantial rise,with estimates indicating a growth from 55 million in 2019 to a staggering 139 million by the year 2050.Among the various forms of dementia.Alzheimer's disease(AD)stands out as the predominant and most prevalent.展开更多
Introduction:TAU isoforms as disease mediators:The microtubule-associated protein TAU is predominantly present in the axons of neurons under physiological conditions.In Alzheimer’s disease(AD)and related tauopathies,...Introduction:TAU isoforms as disease mediators:The microtubule-associated protein TAU is predominantly present in the axons of neurons under physiological conditions.In Alzheimer’s disease(AD)and related tauopathies,TAU also mislocalizes("TAU missorting")to the soma and the dendrites,where it eventually forms aggregates,the so-called neurofibrillary tangles(for review see Zimmer-Bensch and Zempel,2021;Zempel,2023).展开更多
In the ever-evolving landscape of Alzheimer’s treatment,lecanemab(Leqembi)has emerged as a promising drug.Unlike conventional therapies that merely alleviate symptoms,lecanemab is a humanized monoclonal antibody with...In the ever-evolving landscape of Alzheimer’s treatment,lecanemab(Leqembi)has emerged as a promising drug.Unlike conventional therapies that merely alleviate symptoms,lecanemab is a humanized monoclonal antibody with a distinct focus.It targets protofibrils,insoluble fibrils,amyloid oligomers,and soluble amyloid-beta protofibrils,which are known to be especially damaging to neurons,with high accuracy.展开更多
Although many causes of Alzheimer’s disease(AD)may exist,both the original amyloid cascade and tau hypotheses posit that abnormal misfolding and accumulation of amyloid-β(Aβ)and tau protein is the central event cau...Although many causes of Alzheimer’s disease(AD)may exist,both the original amyloid cascade and tau hypotheses posit that abnormal misfolding and accumulation of amyloid-β(Aβ)and tau protein is the central event causing the pathology.However,that conclusion could be only partly true,and there is conflicting evidence about the role of both proteins in AD,being able to precede and influence one another.Some researchers argue that these proteins are mere executors rather than primary causes of pathology.Therefore,there have been continuing refinements of both hypotheses,with alternative explanations proposed.Aβand tau proteins may be independently involved in specific neurotoxic pathways;yet there may be other crucial processes going on in early AD.Moreover,accumulating evidence suggests that Aβand tau act synergistically,rather than additively in disease onset(Jeremic et al.,2021,2023a).展开更多
文摘Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults.Pathogenic factors,such as oxidative stress,an increase in acetylcholinesterase activity,mitochondrial dysfunction,genotoxicity,and neuroinflammation are present in this syndrome,which leads to neurodegeneration.Neurodegenerative pathologies such as Alzheimer’s disease are considered late-onset diseases caused by the complex combination of genetic,epigenetic,and environmental factors.There are two main types of Alzheimer’s disease,known as familial Alzheimer’s disease(onset<65 years)and late-onset or sporadic Alzheimer’s disease(onset≥65 years).Patients with familial Alzheimer’s disease inherit the disease due to rare mutations on the amyloid precursor protein(APP),presenilin 1 and 2(PSEN1 and PSEN2)genes in an autosomaldominantly fashion with closely 100%penetrance.In contrast,a different picture seems to emerge for sporadic Alzheimer’s disease,which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology.Importantly,the fundamental pathophysiological mechanisms driving Alzheimer’s disease are interfaced with epigenetic dysregulation.However,the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer’s disease or following injury or stroke in humans.In recent years,there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer’s disease.Through epigenetic mechanisms,such as DNA methylation,non-coding RNAs,histone modification,and chromatin conformation regulation,natural compounds appear to exert neuroprotective effects.While we do not purport to cover every in this work,we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer’s disease-related genes.
基金supported by the Community Development Office of Hunan Provincial Science and Technology DepartmentChina,Nos.2020SK53613(to DH),21JJ31006(to DH)the Fundamental Research Funds of Central South University,Nos.CX20220375(to TX),2023zzts215(to MZ)。
文摘Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.
文摘Highly specific interactions between biomolecules,such as antigen-antibody,protein-ligand,or nucleic acid base pair complementary are on the basis of the organization of complex organisms.The same principles may be tentatively used in molecular medicine for diagnosis and therapeutics.A molecule can be designed to selectively bind a protease and thereby inhibit the production of a peptide that forms toxic aggregates in the brain or an antibody may be produced to bind specifically to that peptide for detection or clearance purposes.Unfortunately,interference in biological systems is not that simple.For a start there is the inhibition of the physiological role of the protease;moreover,several cleavage fragments may be produced,which may continue to diverge due to putative post-translational modification and self-assembly processes,hiding the toxic target in a“soup”of peptide species varying in size,structure and chemical composition.A perspective of the current status and challenges in targeting peptide species for diagnosis and treatment in the context of Alzheimer’s disease is given.
基金supported by several grant agencies as stated in the full paper(to LT)。
文摘Recent progress in the treatment of Alzheimer’s disease(AD)using antibodies against amyloid sustains amyloid generation as a key process in AD.Amyloid formation starts with two amyloidbeta(Aβ)molecules interacting(dimer formation)followed by an accelerating build-up of socalled protofibrils,which turn into fibrils,which accumulate in the characteristic plaques.
基金supported by a Lee Kong Chian School of Medicine Dean’s Postdoctoral Fellowship(021207-00001)from Nanyang Technological University Singaporea Mistletoe Research Fellowship(022522-00001)from the Momental Foundation USA(to CHL).
文摘Neuronal necroptosis-an emerging form of regulated cell death associated with neuroinflammatory signaling:Alzheimer’s disease(AD)is characterized by the presence of extracellular amyloid-β(Aβ)plaques and intracellular tau neurofibrillary tangles as well as progressive neuronal loss.Recent evidence has suggested that prolonged neuroinflammation with increased levels of cytokines,arising from neuronal injury,innate immune responses from glial cells,and peripheral inflammation,leads to neuronal death and AD progression.
文摘Alzheimer’s disease(AD),the most common type of dementia,affects millions of people worldwide,putting a significant strain on healthcare infrastructure and societal resources.AD is characte rized by the build-up of amyloid-beta(Aβ)plaques and neurofibrillary to ngles containing hyperphosphorylated tau protein.
基金a recipient of the EM BO Short-Term Fellowship(grant9584)a recipient of a fellowship from the CRT Foundation(1393-2017)a grant FAR-2019 from The Universitàdel Piemonte Orientale(to DL)。
文摘Alzheimer's disease(AD)is the most frequent,form of dementia in elderly people and is an incurable disease with an exponentially growing number of cases.Extracellular deposition of amyloid-β(Aβ)plaques and intraneuronal formation of neurofibrillary tangles represent neuropathological hallmarks of AD.
基金supported by grants from the Alzheimer’s Association Research Grant(to GC)Olle Engkvists Stiftelse(to GC)+10 种基金the Petrus and Augusta Hedlunds Stiftelse(to GC)Ake Wibergs stiftelse(to GC)the Swedish Alzheimer foundation(to GC)the Ahlén Stiftelsens(to GC)Karolinska Institutet Research Foundation Grant(to GC)the Stiftelsen for Gamla Tjanarinnor(to GC)the Stiftelsen Sigurd och Elsa Goljes Minne(to GC)the Loo and Hans Osterman Foundation(to GC)Geriatric Diseases Foundation at Karolinska Institutet(to GC)the Gun and Bertil Stohne’s Foundation(to GC)the Magnus Bergvall Foundation(to GC).
文摘Alzheimer’s disease(AD)is the most prevalent form of dementia,i.e.,progressive memory loss and profound cognitive dysfunction,resulting in a considerable societal burden.At the neuropathological level,the brains of AD patients exhibit amyloid-β(Aβ)plaques,neurofibrillary tangles,and neuroinflammation(Sala Frigerio and De Strooper,2016).
文摘Alzheimer's disease(AD) is a progressive neurodegenerative disease histologically characterized by the presence of extraneuronal plaques,mainly formed by the 42-aminoacid isoform of amyloid-(Aβ_(1-42)),and by intraneuronal neurofibrillary to ngles,mainly formed by the tau protein and its hyperphosphorylated isoforms(p-tau).AD is the most common cause of dementia,with an estimated lifetime risk of about 1 in 10 for men and 1 in 5 for women.
基金supported by the Science and Technology Innovation 2030-Major Projects,No.2022ZD021 1 600the National Natural Science Foundation of China,Nos.82271574 and82071204 (all to CX)。
文摘Brain vascular dysfunction in Alzheimer s disease(AD) pathogenesis has become increasingly clea r.Accumulating evidence shows that damaged vascular,including large or small vessels and even neurovascular unit,may accelerate the neuropathological process of AD via disrupting brain hypoperfusion,aberrant angiogenesis,and neuroinflammatory response,etc.Thus,vascular dysfunction makes a substantially contribution to the cognitive decline of AD patients.
基金supported by NIH grants RF1NS126406 and R21NS130326by a generous gift from the Binder Foundation (to GB)
文摘Over 55 million people globally live with Alzheimer’s disease(AD)or related dementias(ADRD)and the number is expected to double every twenty years.Unt i l recent l y,onl y symptomatic treatments were available to patients with AD,including acetylcholine esterase inhibitors,of which the last one,galantamine,was approved by the US Food and Drug Administration(FDA)in 2001.
文摘Loneliness is classically defined as a result of perceiving a discrepancy between the desired quantity and quality of one's social life and actual social relationships(Perlman and Peplau,1984).Lifespan research has indicated older adults are among the highest risk for experiencing loneliness because their social network size decreases more frequently than that of younger adults.
基金the following financial support grant FAR-2019 to DL from The Universita del Piemonte Orientale。
文摘Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and society.Neuropathological hallmarks of AD,evident in postmortem AD brains,include a massive loss of the grey matter in the neocortex,extracellular deposition of amyloid-β(Aβ)in the form of senile plaques and cerebrovascular amyloid angiopathy,and intra-neuronal accumulation of neurofibrillary tangles,formed by hyper-phosphorylated tau protein.
基金supported by grants from the Macao Science and Technology Development Fund(Project code:002/2023/ALC)Foshan Medicine Dengfeng Project of China 2019-2021(to BYKL).
文摘The critical role of calcium dyshomeostasis in the pathogenesis of Alzheimer’s disease(AD):AD is a progressive neurodegenerative disease characterized by cognitive decline,memory impairment,and behavioral changes.With an estimated 50 million people being affected worldwide,the incidence of AD is constantly increasing globally.The hallmark of AD is the accumulation of amyloid-beta protein(Aβ)in the form of amyloid plaques and hyperphosphorylated tau protein in the form of neurofibrillary tangles.However,increasing evidence suggests that calcium ion(Ca2+)dysregulation also plays a crucial role in the pathogenesis of AD(Calvo-Rodriguez and Bacskai,2021).As a key second messenger,Ca2+regulates a wide range of cellular processes,including the release of neurotransmitters,gene expression,and cell death.Ca^(2+)also regulates the activity of Calcium/calmodulin-dependent protein kinase II,which is critical for synaptic plasticity,learning,and memory(Kaushik et al.,2022).Alternation in the Ca^(2+)signal is an early event in the pathogenesis of AD,which can lead to synaptic dysfunction,neuronal loss,and cognitive impairment.
文摘Dementia is a devastating syndrome characterized by memory problems,confusion,and behavior changes that prevent people from performing everyday activities.It is the leading cause of dependency and disability amongst older people,resulting in a global economic cost of ~$1.3 trillion.Around 58 million people are currently afflicted by dementia worldwide,with Alzheimer s disease(AD) causing most(60-70%) of these cases.
基金supported by NIHR01 NS103981 and R01CA273586 to CW。
文摘While extensive studies have illuminated the impact of Alzheimer's disease(AD) on neuronal survival,there is growing evidence that abnormal postnatal neurogenesis in early AD brains contributes to disease progression.Postnatal neurogenesis serves as a mechanism to replace dead or damaged neurons.New neurons generated from neural stem cells(NSCs) in the subgranular zone(SGZ) of the dentate gyrus integrate into the existing hippocampal circuit.
基金supported by grants PID2020-115823-GB100 funded by MCIN/AEI/10.13039/501100011033SBPLY/21/180501/000150 funded by JCCM/ERDF-A way of making Europe+1 种基金2022-GRIN-34354 grant by UCLM/ERDF intramural funding to LJD and JDNLMargarita Salas Postdoctoral Research Fellow (2021-MS-20549)funded by European Union NextGenerationEU/PRTR。
文摘Due to increasing life expectancy,the amount of people with dementia worldwide is expected to experience a substantial rise,with estimates indicating a growth from 55 million in 2019 to a staggering 139 million by the year 2050.Among the various forms of dementia.Alzheimer's disease(AD)stands out as the predominant and most prevalent.
基金supported by the Deutsche Forschungsgemeinschaft and the Else-Kroner-Fresenius-Stiftung(to HZ)。
文摘Introduction:TAU isoforms as disease mediators:The microtubule-associated protein TAU is predominantly present in the axons of neurons under physiological conditions.In Alzheimer’s disease(AD)and related tauopathies,TAU also mislocalizes("TAU missorting")to the soma and the dendrites,where it eventually forms aggregates,the so-called neurofibrillary tangles(for review see Zimmer-Bensch and Zempel,2021;Zempel,2023).
文摘In the ever-evolving landscape of Alzheimer’s treatment,lecanemab(Leqembi)has emerged as a promising drug.Unlike conventional therapies that merely alleviate symptoms,lecanemab is a humanized monoclonal antibody with a distinct focus.It targets protofibrils,insoluble fibrils,amyloid oligomers,and soluble amyloid-beta protofibrils,which are known to be especially damaging to neurons,with high accuracy.
基金supported by grants PID2020-115823-GB100 funded by MCIN/AEI/10.13039/501100011033,and SBPLY/21/180501/000150 funded by JCCM/ERDF-A way of making Europe,and 2022-GRIN-34354 grant by UCLM/ERDF intramural funding to LJD and JDNL.DJ held a predoctoral fellowship granted by UCLM/ESF“Plan Propio de Investigación.”。
文摘Although many causes of Alzheimer’s disease(AD)may exist,both the original amyloid cascade and tau hypotheses posit that abnormal misfolding and accumulation of amyloid-β(Aβ)and tau protein is the central event causing the pathology.However,that conclusion could be only partly true,and there is conflicting evidence about the role of both proteins in AD,being able to precede and influence one another.Some researchers argue that these proteins are mere executors rather than primary causes of pathology.Therefore,there have been continuing refinements of both hypotheses,with alternative explanations proposed.Aβand tau proteins may be independently involved in specific neurotoxic pathways;yet there may be other crucial processes going on in early AD.Moreover,accumulating evidence suggests that Aβand tau act synergistically,rather than additively in disease onset(Jeremic et al.,2021,2023a).