Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by...Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-β（Aβ） peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the Wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, Wnt signaling activation was proposed as a neuroprotective mechanism against Aβ toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that Wnt signaling is fundamental in amyloid precursor protein（APP） processing and that Wnt dysfunction results in Aβ production and aggregation in vitro. Recent in vivo studies reported that loss of canonical Wnt signaling exacerbates amyloid deposition in a transgenic（Tg） mouse model of AD. Finally, we showed that inhibition of Wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aβ formation and aggregation; indicating that Wnt dysfunction accelerated the onset of AD. More importantly, Wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aβ1–42 production in the hippocampus of wild-type（WT） mice, contributing to the development of an Alzheimer＇s-like neurophatology. Therefore, in this review we highlight the importance of Wnt/β-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical Wnt signaling is a triggering factor of AD.展开更多
Kai Xin San is a Chinese herbal formula composed of Radix Ginseng, Poria, Radix Polygalae and Acorus Tatarinowii Rhizome. It has been used in China for many years for treating amnesia. Kai Xin San ameliorates amyloid-...Kai Xin San is a Chinese herbal formula composed of Radix Ginseng, Poria, Radix Polygalae and Acorus Tatarinowii Rhizome. It has been used in China for many years for treating amnesia. Kai Xin San ameliorates amyloid-β （Aβ） induced cognitive dysfunction and is neuroprotective in vivo, but its precise mechanism remains unclear. Expression of insulin-degrading enzyme （IDE）, which degrades Aβ, is strongly correlated with cognitive function. Here, we injected rats with exogenous Aβ42 （200 μM, 5 μL） into the hippocampus and subsequently administered Kai Xin San （0.54 or 1.08 g/kg/d） intragastrically for 21 consecutive days. Hematoxylin eosin and Nissl staining revealed that Kai Xin San protected neurons against Aβ-induced damage. Furthermore, enzyme linked immunosorbent assay, western blot and polymerase chain reaction results showed that Kai Xin San decreased Aβ42 protein levels and increased expression of IDE protein, but not mRNA, in the hippocampus. Our findings reveal that Kai Xin San facilitates hippocampal Aβ degradation and increases IDE expression, which leads, at least in part, to the alleviation of hippocampal neuron injury in rats.展开更多
Impaired amyloid-β clearance from the brain is a core pathological event in Alzheimer＇s disease.The therapeutic effect of current pharmacotherapies is unsatisfactory,and some treatments cause severe side effects.The...Impaired amyloid-β clearance from the brain is a core pathological event in Alzheimer＇s disease.The therapeutic effect of current pharmacotherapies is unsatisfactory,and some treatments cause severe side effects.The meningeal lymphatic vessels might be a new route for amyloid-β clearance.This study investigated whether promoting dural lymphangiogenesis facilitated the clearance of amyloid-β from the brain.First,human lymphatic endothelial cells were treated with 100 ng/m L recombinant human vascular endothelial growth factor-C（rh VEGF-C） protein.Light microscopy verified that rh VEGF-C,a specific ligand for vascular endothelial growth factor receptor-3（VEGFR-3）,significantly promoted tube formation of human lymphatic endothelial cells in vitro.In an in vivo study,200 μg/m L rh VEGF-C was injected into the cisterna magna of APP/PS1 transgenic mice,once every 2 days,four times in total.Immunofluorescence staining demonstrated high levels of dural lymphangiogenesis in Alzheimer＇s disease mice.One week after rh VEGF-C administration,enzyme-linked immunosorbent assay results showed that levels of soluble amyloid-β were decreased in cerebrospinal fluid and brain.The Morris water maze test demonstrated that spatial cognition was restored.These results indicate that the upregulation of dural lymphangiogenesis facilities amyloid-β clearance from the brain of APP/PS1 mice,suggesting the potential of the VEGF-C/VEGFR-3 signaling pathway as a therapeutic target for Alzheimer＇s disease.展开更多
One of the early pathological hallmarks of Alzheimer's disease(AD) is the deposition of amyloid-β(Aβ) plaques in the brain. There has been a tremendous interest in the development of Aβ plaques imaging probes f...One of the early pathological hallmarks of Alzheimer's disease(AD) is the deposition of amyloid-β(Aβ) plaques in the brain. There has been a tremendous interest in the development of Aβ plaques imaging probes for early diagnosis of AD in the past decades. Optical imaging, particularly near-infrared fluorescence(NIRF) imaging, has emerged as a safe, low cost, real-time, and widely available technique, providing an attractive approach for in vivo detection of Aβ plaques among many different imaging techniques. In this review,we provide a brief overview of the state-of-the-art development of NIRF Aβ probes and their in vitro and in vivo applications with special focus on design strategies and optical, binding, and brain-kinetic properties.展开更多
Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer’s disease(AD)have been made and multifarious novel therapeutic approaches have been developed,AD remains an incurable disease.E...Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer’s disease(AD)have been made and multifarious novel therapeutic approaches have been developed,AD remains an incurable disease.Evidence shows that AD neuropathology occurs decades before clinical presentation.AD is divided into three stages:preclinical stage,mild cognitive impairment(MCI),and AD dementia.In the natural world,some animals,such as non-human primates(NHPs)and canines,can develop spontaneous AD-like dementia.However,most animals do not develop AD.With the development of transgenic techniques,both invertebrate and vertebrate animals have been employed to uncover the mechanisms of AD and study treatment methods.Most AD research focuses on early-onset familial AD(FAD)because FAD is associated with specific genetic mutations.However,there are no well-established late-onset sporadic AD(SAD)animal models because SAD is not directly linked to any genetic mutation,and multiple environmental factors are involved.Moreover,the widely used animal models are not able to sufficiently recapitulate the pathological events that occur in the MCI or preclinical stages.This review summarizes the common models used to study AD,from yeast to NHP models,and discusses the different applications,evaluation methods,and challenges related to AD animal models,as well as prospects for the evolution of future studies.展开更多
The principal pathology of Alzheimer＇s disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile pl aques, which in turn induce neuroinflammation in the brain. Triptolide, a ...The principal pathology of Alzheimer＇s disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile pl aques, which in turn induce neuroinflammation in the brain. Triptolide, a natural extract from the vine-like herb Tripterygium wilfordii Hook F, has potent anti-inflammatory and immunosuppressive efficacy. Therefore, we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer＇s disease. We used 1 or 5 μg/kg/d triptolide to treat APP/PS1 double transgenic mice （aged 4-4.5 months） for 45 days. Unbiased stereology analysis found that triptolide dose-dependent- ly reduced the total number of microglial cells, and transformed microglial cells into the resting state. Further, triptolide （5 μg/kg/d） also reduced the total number of hippocampal astrocytes. Our in vivo test results indicate that triptolide suppresses activation and proliferation of microglial cells and astrocytes in the hippocampus of APP/PS 1 double transgenic mice with Alzheimer＇s disease.展开更多
Alzheimer＇s disease （AD） is an age-related neurodegenerative disorder. The pathology of AD includes amyloid-β （Aβ） deposits in neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau, a...Alzheimer＇s disease （AD） is an age-related neurodegenerative disorder. The pathology of AD includes amyloid-β （Aβ） deposits in neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau, as well as neuronal loss in specific brain regions. Increasing epidemiological and functional neuroimaging evidence indicates that global and regional disruptions in brain metabolism are involved in the pathogenesis of this disease. Aβ precursor protein is cleaved to produce both extracellular and intracellular Aβ, accumulation of which might interfere with the homeostasis of cellular metabolism. Mitochondria are highly dynamic organelles that not only supply the main energy to the cell but also regulate apoptosis. Mitochondrial dysfunction might contribute to Aβ neurotoxicity. In this review, we summarize the pathways ofAβ generation and its potential neurotoxic effects on cellular metabolism and mitochondrial dysfunction.展开更多
The toxicity of amyloid-beta（Aβ） is strongly associated with Alzheimer’s disease（AD）,which has a high incidence in the elderly worldwide.Recent evidence showed that alteration in the activity of N-methyl-D-aspar...The toxicity of amyloid-beta（Aβ） is strongly associated with Alzheimer’s disease（AD）,which has a high incidence in the elderly worldwide.Recent evidence showed that alteration in the activity of N-methyl-D-aspartate receptors（NMDARs） plays a key role in Aβ-induced neurotoxicity.However,the activation of synaptic and extrasynaptic NMDARs has distinct consequences for plasticity,gene regulation,neuronal death,and Aβ production.This review focuses on the dysregulation of synaptic and extrasynaptic NMDARs induced by Aβ.On one hand,Aβ downregulates the synaptic NMDAR response by promoting NMDAR endocytosis,leading to either neurotoxicity or neuroprotection.On the other hand,Aβ enhances the activation of extrasynaptic NMDARs by decreasing neuronal glutamate uptake and inducing glutamate spillover,subsequently causing neurotoxicity.In addition,selective enhancement of synaptic activity by low doses of NMDA,or reduction of extrasynaptic activity by memantine,a non-competitive NMDAR antagonist,halts Aβ-induced neurotoxicity.Therefore,future neuroprotective drugs for AD should aim at both the enhancement of synaptic activity and the disruption of extrasynaptic NMDAR-dependent death signaling.展开更多
基金supported by grants PFB (Basal Financing Program) 12/2007 from the Basal Centre for Excellence in Science and Technology and FONDECYT,No.1120156(to NCI)a pre-doctoral fellowship from the National Commission of Science and Technology of Chile(CONICYT)(to CTR)
文摘Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-β（Aβ） peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the Wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, Wnt signaling activation was proposed as a neuroprotective mechanism against Aβ toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that Wnt signaling is fundamental in amyloid precursor protein（APP） processing and that Wnt dysfunction results in Aβ production and aggregation in vitro. Recent in vivo studies reported that loss of canonical Wnt signaling exacerbates amyloid deposition in a transgenic（Tg） mouse model of AD. Finally, we showed that inhibition of Wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aβ formation and aggregation; indicating that Wnt dysfunction accelerated the onset of AD. More importantly, Wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aβ1–42 production in the hippocampus of wild-type（WT） mice, contributing to the development of an Alzheimer＇s-like neurophatology. Therefore, in this review we highlight the importance of Wnt/β-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical Wnt signaling is a triggering factor of AD.
基金supported by the National Natural Science Foundation of China,No.81303248,81603321the Natural Science Foundation of Heilongjiang Province of China,No.H2015028+1 种基金a grant from the Nursing Program for Young Scholars of Heilongjiang Province of China,No.UNPYSCT-2016116the Scientific Research Fund for Doctors of Qiqihar Medical University in China,No.QY2016B-09
文摘Kai Xin San is a Chinese herbal formula composed of Radix Ginseng, Poria, Radix Polygalae and Acorus Tatarinowii Rhizome. It has been used in China for many years for treating amnesia. Kai Xin San ameliorates amyloid-β （Aβ） induced cognitive dysfunction and is neuroprotective in vivo, but its precise mechanism remains unclear. Expression of insulin-degrading enzyme （IDE）, which degrades Aβ, is strongly correlated with cognitive function. Here, we injected rats with exogenous Aβ42 （200 μM, 5 μL） into the hippocampus and subsequently administered Kai Xin San （0.54 or 1.08 g/kg/d） intragastrically for 21 consecutive days. Hematoxylin eosin and Nissl staining revealed that Kai Xin San protected neurons against Aβ-induced damage. Furthermore, enzyme linked immunosorbent assay, western blot and polymerase chain reaction results showed that Kai Xin San decreased Aβ42 protein levels and increased expression of IDE protein, but not mRNA, in the hippocampus. Our findings reveal that Kai Xin San facilitates hippocampal Aβ degradation and increases IDE expression, which leads, at least in part, to the alleviation of hippocampal neuron injury in rats.
基金supported by the National Natural Science Foundation of China,No.31371130 and 31600836the Special Foundation of Education Department of Guangdong Province of China+1 种基金the Medical Scientific Research Foundation of Guangdong Province of China,No.2013-159the Foundation of Medical Science and Technology Research of Guangdong Province of China,No.A2016273
文摘Impaired amyloid-β clearance from the brain is a core pathological event in Alzheimer＇s disease.The therapeutic effect of current pharmacotherapies is unsatisfactory,and some treatments cause severe side effects.The meningeal lymphatic vessels might be a new route for amyloid-β clearance.This study investigated whether promoting dural lymphangiogenesis facilitated the clearance of amyloid-β from the brain.First,human lymphatic endothelial cells were treated with 100 ng/m L recombinant human vascular endothelial growth factor-C（rh VEGF-C） protein.Light microscopy verified that rh VEGF-C,a specific ligand for vascular endothelial growth factor receptor-3（VEGFR-3）,significantly promoted tube formation of human lymphatic endothelial cells in vitro.In an in vivo study,200 μg/m L rh VEGF-C was injected into the cisterna magna of APP/PS1 transgenic mice,once every 2 days,four times in total.Immunofluorescence staining demonstrated high levels of dural lymphangiogenesis in Alzheimer＇s disease mice.One week after rh VEGF-C administration,enzyme-linked immunosorbent assay results showed that levels of soluble amyloid-β were decreased in cerebrospinal fluid and brain.The Morris water maze test demonstrated that spatial cognition was restored.These results indicate that the upregulation of dural lymphangiogenesis facilities amyloid-β clearance from the brain of APP/PS1 mice,suggesting the potential of the VEGF-C/VEGFR-3 signaling pathway as a therapeutic target for Alzheimer＇s disease.
基金supported by the Fundamental Research Funds for the Central Universities and East China University of Science and Technology (start-up funds, Wei Wang)the China 111 Project (Grant B07023, Wei Wang)
文摘One of the early pathological hallmarks of Alzheimer's disease(AD) is the deposition of amyloid-β(Aβ) plaques in the brain. There has been a tremendous interest in the development of Aβ plaques imaging probes for early diagnosis of AD in the past decades. Optical imaging, particularly near-infrared fluorescence(NIRF) imaging, has emerged as a safe, low cost, real-time, and widely available technique, providing an attractive approach for in vivo detection of Aβ plaques among many different imaging techniques. In this review,we provide a brief overview of the state-of-the-art development of NIRF Aβ probes and their in vitro and in vivo applications with special focus on design strategies and optical, binding, and brain-kinetic properties.
基金supported by the National Science and Technology Innovation 2030-Major Program of“Brain Science and Brain-Like Research”(2022ZD0211800)National Natural Science Foundation of China(NSFC)General Research Grants(81971679,32020103007,32088101,21727806)+1 种基金Ministry of Science and Technology(2018YFA0507600,2017YFA0503600)Qidong-PKU SLS Innovation Fund(2016000663,2017000246)。
文摘Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer’s disease(AD)have been made and multifarious novel therapeutic approaches have been developed,AD remains an incurable disease.Evidence shows that AD neuropathology occurs decades before clinical presentation.AD is divided into three stages:preclinical stage,mild cognitive impairment(MCI),and AD dementia.In the natural world,some animals,such as non-human primates(NHPs)and canines,can develop spontaneous AD-like dementia.However,most animals do not develop AD.With the development of transgenic techniques,both invertebrate and vertebrate animals have been employed to uncover the mechanisms of AD and study treatment methods.Most AD research focuses on early-onset familial AD(FAD)because FAD is associated with specific genetic mutations.However,there are no well-established late-onset sporadic AD(SAD)animal models because SAD is not directly linked to any genetic mutation,and multiple environmental factors are involved.Moreover,the widely used animal models are not able to sufficiently recapitulate the pathological events that occur in the MCI or preclinical stages.This review summarizes the common models used to study AD,from yeast to NHP models,and discusses the different applications,evaluation methods,and challenges related to AD animal models,as well as prospects for the evolution of future studies.
基金supported by China Postdoctoral Science Foundation,No.2016M590757the Postdoctoral Science Foundation of Xiangya Hospital of Central South University of China,No.20+4 种基金the Hunan Provincial Natural Science Foundation of China,No.2015JJ6010a grant from the Basic Research Program of Science and Technology Commission Foundation of Hunan Province of China,No.2015JC3059the Project Fund of the Department of Education in Hunan Province of China,No.15A023,13C1107the Scientific Research Project Fund of Health Department of Hunan Province of China,No.B2011-071,B2016096a grant from the Construction Program of the Key Discipline in Hunan Province of China
文摘The principal pathology of Alzheimer＇s disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile pl aques, which in turn induce neuroinflammation in the brain. Triptolide, a natural extract from the vine-like herb Tripterygium wilfordii Hook F, has potent anti-inflammatory and immunosuppressive efficacy. Therefore, we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer＇s disease. We used 1 or 5 μg/kg/d triptolide to treat APP/PS1 double transgenic mice （aged 4-4.5 months） for 45 days. Unbiased stereology analysis found that triptolide dose-dependent- ly reduced the total number of microglial cells, and transformed microglial cells into the resting state. Further, triptolide （5 μg/kg/d） also reduced the total number of hippocampal astrocytes. Our in vivo test results indicate that triptolide suppresses activation and proliferation of microglial cells and astrocytes in the hippocampus of APP/PS 1 double transgenic mice with Alzheimer＇s disease.
基金supported by the National Natural Science Foundation of China(31071512)the Subsidy for Outstanding People of Beijing Municipality, China (2012D005022000006)the Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality, China [PHR(IHLB), PHR20090514]
文摘Alzheimer＇s disease （AD） is an age-related neurodegenerative disorder. The pathology of AD includes amyloid-β （Aβ） deposits in neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau, as well as neuronal loss in specific brain regions. Increasing epidemiological and functional neuroimaging evidence indicates that global and regional disruptions in brain metabolism are involved in the pathogenesis of this disease. Aβ precursor protein is cleaved to produce both extracellular and intracellular Aβ, accumulation of which might interfere with the homeostasis of cellular metabolism. Mitochondria are highly dynamic organelles that not only supply the main energy to the cell but also regulate apoptosis. Mitochondrial dysfunction might contribute to Aβ neurotoxicity. In this review, we summarize the pathways ofAβ generation and its potential neurotoxic effects on cellular metabolism and mitochondrial dysfunction.
基金supported by the National Natural Science Foundation of China(81371223 and 81371437)the Research Fund for the Doctoral Program of Higher Education of China(20122105110010)the Science and Technology Project of Liaoning Province,China(2011226006)
文摘The toxicity of amyloid-beta（Aβ） is strongly associated with Alzheimer’s disease（AD）,which has a high incidence in the elderly worldwide.Recent evidence showed that alteration in the activity of N-methyl-D-aspartate receptors（NMDARs） plays a key role in Aβ-induced neurotoxicity.However,the activation of synaptic and extrasynaptic NMDARs has distinct consequences for plasticity,gene regulation,neuronal death,and Aβ production.This review focuses on the dysregulation of synaptic and extrasynaptic NMDARs induced by Aβ.On one hand,Aβ downregulates the synaptic NMDAR response by promoting NMDAR endocytosis,leading to either neurotoxicity or neuroprotection.On the other hand,Aβ enhances the activation of extrasynaptic NMDARs by decreasing neuronal glutamate uptake and inducing glutamate spillover,subsequently causing neurotoxicity.In addition,selective enhancement of synaptic activity by low doses of NMDA,or reduction of extrasynaptic activity by memantine,a non-competitive NMDAR antagonist,halts Aβ-induced neurotoxicity.Therefore,future neuroprotective drugs for AD should aim at both the enhancement of synaptic activity and the disruption of extrasynaptic NMDAR-dependent death signaling.
