Dysregulated glial genes in Alzheimer's disease are essential for homeostatic plasticity: Evidence from integrative epigenetic and single cell analyses.
Dysregulated glial genes in Alzheimer's disease are essential for homeostatic plasticity: Evidence from integrative epigenetic and single cell analyses.
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作者：
突触的稳态可塑性是维持神经系统内突触和神经功能稳定的基本调节机制。在阿尔茨海默病(AD)的发展过程中，体内平衡调节的受损与突触的不稳定有关。最近神经系统的表观遗传学和转录学特征揭示了关于大脑老化和神经退行性疾病发病机制的复杂分子细节。然而，AD中不同细胞类型的异常表观遗传和转录改变如何影响突触的内稳态可塑性仍有待阐明。不同类型的神经胶质细胞在调节突触功能方面发挥着关键作用，无论是在衰老过程中还是在阿尔茨海默病的背景下。在这里，我们利用计算分析和电生理学方法，在果蝇中研究了AD中神经胶质细胞组蛋白乙酰化和转录组的失调对突触稳态可塑性的影响。通过整合来自同一AD患者队列的SnRNA-seq和H3K9ac芯片-seq数据，我们准确地定位了组蛋白乙酰化在转录上改变的细胞类型特异性签名基因。随后，我们研究了这些神经胶质基因在调节果蝇突触前内稳态增强中的作用。值得注意的是，通过我们的计算方法确定了9个胶质特异性基因，它们是H3K9ac和转录调控失调的靶标，被发现对果蝇突触内稳态可塑性的调节至关重要。我们的遗传学证据表明，阿尔茨海默病患者胶质细胞转录异常改变与神经系统内环境平衡可塑性受损有关。综上所述，我们的综合计算和遗传学研究强调了特定的神经胶质基因是阿尔茨海默病患者体内平衡失衡的潜在关键因素。我们整合了两项关于阿尔茨海默病(AD)患者中H3K9ac芯片-seq和SnRNA-seq的研究数据，并确定了H3K9ac直接靶向的基因和AD中细胞类型特定的deg。我们研究了9个胶质细胞特异的DEG，以研究它们在果蝇突触内稳态可塑性中的作用。所有这九个基因都是AD中H3K9ac和胶质细胞degs的靶标，对于体内平衡可塑性是必需的，突显了胶质细胞在稳定AD突触功能中的关键作用。
Synaptic homeostatic plasticity is a foundational regulatory mechanism that maintains the stability of synaptic and neural functions within the nervous system. Impairment of homeostatic regulation has been linked to synapse destabilization during the progression of Alzheimer's disease (AD). Recent epigenetic and transcriptomic characterizations of the nervous system have revealed intricate molecular details about the aging brain and the pathogenesis of neurodegenerative diseases. Yet, how abnormal epigenetic and transcriptomic alterations in different cell types in AD affect synaptic homeostatic plasticity remains to be elucidated. Various glial cell types play critical roles in modulating synaptic functions both during the aging process and in the context of AD. Here, we investigated the impact of glial dysregulation of histone acetylation and transcriptome in AD on synaptic homeostatic plasticity, using computational analysis combined with electrophysiological methods in Drosophila. By integrating snRNA‐seq and H3K9ac ChIP‐seq data from the same AD patient cohort, we pinpointed cell type‐specific signature genes that were transcriptionally altered by histone acetylation. We subsequently investigated the role of these glial genes in regulating presynaptic homeostatic potentiation in Drosophila. Remarkably, nine glial‐specific genes, which were identified through our computational method as targets of H3K9ac and transcriptional dysregulation, were found to be crucial for the regulation of synaptic homeostatic plasticity in Drosophila. Our genetic evidence connects abnormal glial transcriptomic changes in AD with the impairment of homeostatic plasticity in the nervous system. In summary, our integrative computational and genetic studies highlight specific glial genes as potential key players in the homeostatic imbalance observed in AD. We integrated data from two studies on H3K9ac ChIP‐seq and snRNA‐seq in Alzheimer's disease (AD) patients and identified genes that are both directly targeted by H3K9ac and are cell type‐specific DEGs in AD. We studied nine glial‐specific DEGs to investigate their roles in synaptic homeostatic plasticity in Drosophila. All nine of these genes, targets of H3K9ac and glial DEGs in AD, are necessary for homeostatic plasticity, highlighting the critical role of glia in stabilizing synaptic function in AD.
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影响因子：
25
作者：
Habib, Naomi;McCabe, Cristin;Medina, Sedi;Varshavsky, Miriam;Kitsberg, Daniel;Dvir-Szternfeld, Raz;Green, Gilad;Dionne, Danielle;Nguyen, Lan;Marshall, Jamie L.;Chen, Fei;Zhang, Feng;Kaplan, Tommy;Regev, Aviv;Schwartz, Michal
通讯作者：
Schwartz, Michal
影响因子：
64.5
作者：
Davie K;Janssens J;Koldere D;De Waegeneer M;Pech U;Kreft Ł;Aibar S;Makhzami S;Christiaens V;Bravo González-Blas C;Poovathingal S;Hulselmans G;Spanier KI;Moerman T;Vanspauwen B;Geurs S;Voet T;Lammertyn J;Thienpont B;Liu S;Konstantinides N;Fiers M;Verstreken P;Aerts S
通讯作者：
Aerts S
影响因子：
25
作者：
Nativio R;Donahue G;Berson A;Lan Y;Amlie-Wolf A;Tuzer F;Toledo JB;Gosai SJ;Gregory BD;Torres C;Trojanowski JQ;Wang LS;Johnson FB;Bonini NM;Berger SL
通讯作者：
Berger SL
DOI：
10.1126/science.1179685
发表时间：
2009-11-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Dickman DK;Davis GW
通讯作者：
Davis GW
DOI：
10.1038/s41572-021-00269-y
发表时间：
2021-05-13
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
Knopman DS;Amieva H;Petersen RC;Chételat G;Holtzman DM;Hyman BT;Nixon RA;Jones DT
通讯作者：
Jones DT