Background: Amyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging an...Background: Amyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging and cognitive impairment. However, it remains blurred whether, in theAD brains, Aβ accelerates the neuronal senescence and whether this senescence, in turn, impairs the cognitive function. This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model. Methods: The 5XFAD mice and age-matched wild type mice, both raised from 1 to 18 months, were enrolled in the study. The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction. Cognitive perfom3ance of the mice was evaluated by Y-maze and Morris water maze tests. Oligomeric Aβ(oAβ) (1-42) was applied to culture primary neurons to simulate the in vivo manifestation. Aging-related proteins were detected by Western blotting analysis and immunofluorescence. Results: In 5XFAD mice, of all the DEGs, the senescence-associated marker p16 was most significantly increased, even at the early age. It was mainly localized in neurons, with a marginal expression in astrocytes (labeled as glutamine synthetase), nil expression in activated microglia (labeled as lba1), and negatively correlated with the spatial cognitive impairments of 5XFAD mice. oAβ (1-42) induced the production of senescence-related protein p1 6, but not p53 in vitro, which was in line with the in vivo manifestation. Conclusions: oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for A D population.展开更多
Background: Amyloid β (Aβ) deposits and the endoplasmic reticulum stress (ERS) are both well established in the development and progression of Alzheimer's disease (AD). However, the mechanism and role of Aβ...Background: Amyloid β (Aβ) deposits and the endoplasmic reticulum stress (ERS) are both well established in the development and progression of Alzheimer's disease (AD). However, the mechanism and role of Aβ-induced ERS in AD-associated pathological progression remain to be elucidated. Methods: The five familial AD (5×FAD) mice and wild-type (WT) mice aged 2, 7, and 12 months were used in the present study. Monis water maze test was used to evaluate their cognitive performance, lmmunofluorescence and Western blot analyses were used to examine the dynamic changes of pro-apoptotic (CCAAT/enhancer-binding protein homologous protein [CHOP] and cleaved caspase-12) and anti-apoptotic factors (chaperone glucose-regulated protein [GRP] 78 and endoplasmic reticulum-associated protein degradation-associated ubiquitin ligase synovial apoptosis inhibitor 1 [SYVN 1]) in the ERS-associated unfolded protein response (UPR) pathway. Results: Compared with age-matched WT mice, 5 xFAD mice showed higher cleaved caspase-3, lower neuron-positive staining at the age of 12 months, but earlier cognitive deficit at the age of 7 months (all P 〈 0.05). Interestingly, for 2-month-old 5×FAD mice, the related proteins involved in the ERS-associated UPR pathway, including CHOP, cleaved caspase-12, GRP 78, and SYVN 1, were significantly increased when compared with those in age-matched WT mice (all P 〈 0.05). Moreover, ERS occurred mainly in neurons, not in astrocytes. Conclusions: These findings suggest that compared with those of age-matched WT mice, ERS-associated pro-apoptotic and anti-apoptotic proteins are upregulated in 2-month-old 5×FAD mice, consistent with intracellular Aβ aggregation in neurons.展开更多
Background:Early diagnosis assumes a vital role in an effective treatment of Alzheimer's disease (AD).Most of the current studies can only make anAD diagnosis after the manifestation of typical clinical symptoms.T...Background:Early diagnosis assumes a vital role in an effective treatment of Alzheimer's disease (AD).Most of the current studies can only make anAD diagnosis after the manifestation of typical clinical symptoms.The present study aimed to investigate typical and other biomarkers of AD to find a possible early biomarker.Methods:A total of 14 5XFAD mice (at 3 and 6 months old),with 14 age-matched wild-type (WT) mice as control,were enrolled in this case-control study.Morris water maze test was performed to evaluate the cognitive function;buried food pellet test and olfactory maze test were employed to investigate the olfactory function;immunofluorescence to detect amyloid deposition and positron emission tomography to examine 2-deoxy-2-(18F) fluoro-D-glucose ([18F]-FDG) uptake in the hippocampus and cerebral cortex.Results:With the increasing age,cognitive performance (P =0.0262) and olfactory function were significantly deteriorated (day 1 P =0.0012,day 2 P =0.0031,day 3 P =0.0160,respectively) and the (18F)-FDG uptake was markedly decreased in multi-cerebral regions including the olfactory bulb (P 〈 0.0001),hippocampus (P =0.0121),and cerebral cortex (P 〈 0.0001).Of note,in 3-month-old 5XFAD mice,a significant decline of (18F)-FDG uptake in the olfactory bulb was found when compared with that of age-matched WT mice (P =0.023) while no significant difference was present when the uptakes in other cerebral regions were compared.Conclusions:The decline of (18F)-FDG uptake in the olfactory bulb occurs earlier than other incidents,serving as an earlier in vivo biological marker of AD in 5XFAD mice and making early diagnosis of AD possibly.展开更多
During recent years, major advances have been made in neuroscience, i.e., asynchronous release, three-dimensional structural data sets, saliency maps, magnesium in brain research, and new functional roles of long non-...During recent years, major advances have been made in neuroscience, i.e., asynchronous release, three-dimensional structural data sets, saliency maps, magnesium in brain research, and new functional roles of long non-coding RNAs. Especially, the development of optogenetic technology provides access to important information about relevant neural circuits by allowing the activation of specific neurons in awake mammals and directly observing the resulting behavior. The Grand Research Plan for Neural Circuits of Emotion and Memory was launched by the National Natural Science Foundation of China. It takes emotion and memory as its main objects, making the best use of cutting-edge technologies from medical science, life science and information science. In this paper, we outline the current status of neural circuit studies in China and the technologies and methodologies being applied, as well as studies related to the impairments of emotion and memory. In this phase, we are making efforts to repair the current deficiencies by making adjustments, mainly involving four aspects of core scientific issues to investigate these circuits at multiple levels. Five research directions have been taken to solve important scientific problems while the Grand Research Plan is implemented. Future research into this area will be multimodal, incorporating a range of methods and sciences into each project. Addressing these issues will ensure a bright future, major discoveries, and a higher level of treatment for all affected by debilitating brain illnesses.展开更多
基金We would like to thank teacher Hong-Zhi Huang from College of Foreign Languages of Fujian Medical University for the kindly help of text modifications and retouching of this paper. This study was supported by grants from National Natural Science Fotmdation of China (No. 81200991 and No. 81571257), Fujian Provincial Natural Science Foundation (No. 2015J01398), Fujian Provincial New Century Excellent Talents Support Program, China (JA13131), and Young and Middle-aged Talent Training Key Project in Health System of Fujian Province (2014-ZQN-ZD- 11).
文摘Background: Amyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging and cognitive impairment. However, it remains blurred whether, in theAD brains, Aβ accelerates the neuronal senescence and whether this senescence, in turn, impairs the cognitive function. This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model. Methods: The 5XFAD mice and age-matched wild type mice, both raised from 1 to 18 months, were enrolled in the study. The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction. Cognitive perfom3ance of the mice was evaluated by Y-maze and Morris water maze tests. Oligomeric Aβ(oAβ) (1-42) was applied to culture primary neurons to simulate the in vivo manifestation. Aging-related proteins were detected by Western blotting analysis and immunofluorescence. Results: In 5XFAD mice, of all the DEGs, the senescence-associated marker p16 was most significantly increased, even at the early age. It was mainly localized in neurons, with a marginal expression in astrocytes (labeled as glutamine synthetase), nil expression in activated microglia (labeled as lba1), and negatively correlated with the spatial cognitive impairments of 5XFAD mice. oAβ (1-42) induced the production of senescence-related protein p1 6, but not p53 in vitro, which was in line with the in vivo manifestation. Conclusions: oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for A D population.
基金This work was supported by grants from the National Natural Science Foundation of China (No. 91232709, No. 811171216, and No. 81161120496 for Prof. Xiao-Chun Chen, and No. 81200991 for Prof. Xiao-Dong Pan) and the National and Fujian Province's Key Clinical Specialty Discipline Construction Programs.
文摘Background: Amyloid β (Aβ) deposits and the endoplasmic reticulum stress (ERS) are both well established in the development and progression of Alzheimer's disease (AD). However, the mechanism and role of Aβ-induced ERS in AD-associated pathological progression remain to be elucidated. Methods: The five familial AD (5×FAD) mice and wild-type (WT) mice aged 2, 7, and 12 months were used in the present study. Monis water maze test was used to evaluate their cognitive performance, lmmunofluorescence and Western blot analyses were used to examine the dynamic changes of pro-apoptotic (CCAAT/enhancer-binding protein homologous protein [CHOP] and cleaved caspase-12) and anti-apoptotic factors (chaperone glucose-regulated protein [GRP] 78 and endoplasmic reticulum-associated protein degradation-associated ubiquitin ligase synovial apoptosis inhibitor 1 [SYVN 1]) in the ERS-associated unfolded protein response (UPR) pathway. Results: Compared with age-matched WT mice, 5 xFAD mice showed higher cleaved caspase-3, lower neuron-positive staining at the age of 12 months, but earlier cognitive deficit at the age of 7 months (all P 〈 0.05). Interestingly, for 2-month-old 5×FAD mice, the related proteins involved in the ERS-associated UPR pathway, including CHOP, cleaved caspase-12, GRP 78, and SYVN 1, were significantly increased when compared with those in age-matched WT mice (all P 〈 0.05). Moreover, ERS occurred mainly in neurons, not in astrocytes. Conclusions: These findings suggest that compared with those of age-matched WT mice, ERS-associated pro-apoptotic and anti-apoptotic proteins are upregulated in 2-month-old 5×FAD mice, consistent with intracellular Aβ aggregation in neurons.
基金grants from the National Natural Science Foundation of China (No. 81171216 and No. 91232709), and the Key Clinical Specialty Discipline Construction Program of Fujian and Nation, China.
文摘Background:Early diagnosis assumes a vital role in an effective treatment of Alzheimer's disease (AD).Most of the current studies can only make anAD diagnosis after the manifestation of typical clinical symptoms.The present study aimed to investigate typical and other biomarkers of AD to find a possible early biomarker.Methods:A total of 14 5XFAD mice (at 3 and 6 months old),with 14 age-matched wild-type (WT) mice as control,were enrolled in this case-control study.Morris water maze test was performed to evaluate the cognitive function;buried food pellet test and olfactory maze test were employed to investigate the olfactory function;immunofluorescence to detect amyloid deposition and positron emission tomography to examine 2-deoxy-2-(18F) fluoro-D-glucose ([18F]-FDG) uptake in the hippocampus and cerebral cortex.Results:With the increasing age,cognitive performance (P =0.0262) and olfactory function were significantly deteriorated (day 1 P =0.0012,day 2 P =0.0031,day 3 P =0.0160,respectively) and the (18F)-FDG uptake was markedly decreased in multi-cerebral regions including the olfactory bulb (P 〈 0.0001),hippocampus (P =0.0121),and cerebral cortex (P 〈 0.0001).Of note,in 3-month-old 5XFAD mice,a significant decline of (18F)-FDG uptake in the olfactory bulb was found when compared with that of age-matched WT mice (P =0.023) while no significant difference was present when the uptakes in other cerebral regions were compared.Conclusions:The decline of (18F)-FDG uptake in the olfactory bulb occurs earlier than other incidents,serving as an earlier in vivo biological marker of AD in 5XFAD mice and making early diagnosis of AD possibly.
文摘During recent years, major advances have been made in neuroscience, i.e., asynchronous release, three-dimensional structural data sets, saliency maps, magnesium in brain research, and new functional roles of long non-coding RNAs. Especially, the development of optogenetic technology provides access to important information about relevant neural circuits by allowing the activation of specific neurons in awake mammals and directly observing the resulting behavior. The Grand Research Plan for Neural Circuits of Emotion and Memory was launched by the National Natural Science Foundation of China. It takes emotion and memory as its main objects, making the best use of cutting-edge technologies from medical science, life science and information science. In this paper, we outline the current status of neural circuit studies in China and the technologies and methodologies being applied, as well as studies related to the impairments of emotion and memory. In this phase, we are making efforts to repair the current deficiencies by making adjustments, mainly involving four aspects of core scientific issues to investigate these circuits at multiple levels. Five research directions have been taken to solve important scientific problems while the Grand Research Plan is implemented. Future research into this area will be multimodal, incorporating a range of methods and sciences into each project. Addressing these issues will ensure a bright future, major discoveries, and a higher level of treatment for all affected by debilitating brain illnesses.