The entorhinal cortex(EC)-hippocampal(HPC)circuit is particularly vulnerable to Alzheimer's disease(AD)pathol-ogy,yet the underlying molecular mechanisms remain unclear.By employing the high-depth sequencing strat...The entorhinal cortex(EC)-hippocampal(HPC)circuit is particularly vulnerable to Alzheimer's disease(AD)pathol-ogy,yet the underlying molecular mechanisms remain unclear.By employing the high-depth sequencing strategy Smart-seq2,we tracked gene expression changes across various neuron types within this circuit at different stages of AD pathology.We observed a decrease in the extent of gene expression changes in AD versus wild-type(WT)mice as the disease advanced.Functionally,we demonstrate that both mitochondrial and ribosomal pathways were increasingly activated,while neuronal pathways were inhibited with AD progression.Our findings indicate that the reduction of EC-stellate cells disrupts Meg3-mediated energy metabolism,contributing to energy dysfunction in AD.Additionally,we identified GFAP-positive neurons as a distinct population of disease-associated neurons,exhibiting a loss of neuronal-like characteristics,alongside the emergence of glia-and stem-like features.The num-ber of GFAP-positive neurons increased with AD progression,a trend consistently observed in both AD model mice and AD patients.In summary,this study identifies and characterizes GFAP-positive neurons as a novel subtype of disease-associated neurons in AD pathology,providing insights into their potential role in disease progression.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.82125009,82330045,32121002,82071185,82172061,and 92149303)the National Key R&D Program of China(Grant Nos.2020YFA0509300,2021YFA0804900,and 2022YFC2703102)+4 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39000000)CAS Project for Young Scientists in Basic Research(YSBR-013),Plans for Major Provincial Science&Technology Projects(202303a07020004)Hefei Comprehensive National Science Center Hefei Brain Project,Research Funds of Center for Advanced Interdisciplinary Science and Biomedicine of IHM(QYZD20220003)the Major Frontier Research Project of the University of Science and Technology of China(LS9100000002)S&T Program of Shijiazhuang(235790429H).
文摘The entorhinal cortex(EC)-hippocampal(HPC)circuit is particularly vulnerable to Alzheimer's disease(AD)pathol-ogy,yet the underlying molecular mechanisms remain unclear.By employing the high-depth sequencing strategy Smart-seq2,we tracked gene expression changes across various neuron types within this circuit at different stages of AD pathology.We observed a decrease in the extent of gene expression changes in AD versus wild-type(WT)mice as the disease advanced.Functionally,we demonstrate that both mitochondrial and ribosomal pathways were increasingly activated,while neuronal pathways were inhibited with AD progression.Our findings indicate that the reduction of EC-stellate cells disrupts Meg3-mediated energy metabolism,contributing to energy dysfunction in AD.Additionally,we identified GFAP-positive neurons as a distinct population of disease-associated neurons,exhibiting a loss of neuronal-like characteristics,alongside the emergence of glia-and stem-like features.The num-ber of GFAP-positive neurons increased with AD progression,a trend consistently observed in both AD model mice and AD patients.In summary,this study identifies and characterizes GFAP-positive neurons as a novel subtype of disease-associated neurons in AD pathology,providing insights into their potential role in disease progression.
