Molecular differences in brain regional vulnerability to aging between males and females.
Molecular differences in brain regional vulnerability to aging between males and females.
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DOI：
10.3389/fnagi.2023.1153251
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发表时间：
2023
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
与衰老相关的认知能力下降与大脑结构变化和突触丧失有关。然而，正常衰老过程中认知能力下降的分子机制尚不清楚。利用来自13个大脑区域的GTEx转录组学数据，我们在男性和女性中发现了与衰老相关的分子改变和细胞类型组成。我们进一步构建了基因共表达网络，并确定了性别共享或特定于男性或女性的衰老相关模块和关键调控因子。男性的海马体和下丘脑等少数大脑区域表现出特定的脆弱性，而女性的小脑半球和前扣带皮层区域表现出比男性更大的脆弱性。免疫反应基因与年龄正相关，而参与神经发生的基因与年龄负相关。在海马体和额叶皮质中发现的衰老相关基因显著富集与阿尔茨海默病（AD）发病机制相关的基因特征。在海马体中，男性特异性共表达模块由关键突触信号调节因子驱动，包括VSNL1、INA、CHN1和KCNH1；而在皮层中，一个女性特有的模块与神经元投射形态发生有关，这是由包括SRPK2、REPS2和FXYD1在内的关键调节因子驱动的。在小脑半球，男性和女性共有的髓鞘相关模块由MOG、ENPP2、MYRF、ANLN、MAG和PLP1等关键调控因子驱动，这些调控因子与AD和其他神经退行性疾病的发生有关。这项综合网络生物学研究系统地识别了男性和女性大脑区域衰老脆弱性的分子特征和网络。这一发现为理解诸如阿尔茨海默病等神经退行性疾病中性别差异的分子机制铺平了道路。
Aging-related cognitive decline is associated with brain structural changes and synaptic loss. However, the molecular mechanisms of cognitive decline during normal aging remain elusive. Using the GTEx transcriptomic data from 13 brain regions, we identified aging-associated molecular alterations and cell-type compositions in males and females. We further constructed gene co-expression networks and identified aging-associated modules and key regulators shared by both sexes or specific to males or females. A few brain regions such as the hippocampus and the hypothalamus show specific vulnerability in males, while the cerebellar hemisphere and the anterior cingulate cortex regions manifest greater vulnerability in females than in males. Immune response genes are positively correlated with age, whereas those involved in neurogenesis are negatively correlated with age. Aging-associated genes identified in the hippocampus and the frontal cortex are significantly enriched for gene signatures implicated in Alzheimer’s disease (AD) pathogenesis. In the hippocampus, a male-specific co-expression module is driven by key synaptic signaling regulators including VSNL1, INA, CHN1 and KCNH1; while in the cortex, a female-specific module is associated with neuron projection morphogenesis, which is driven by key regulators including SRPK2, REPS2 and FXYD1. In the cerebellar hemisphere, a myelination-associated module shared by males and females is driven by key regulators such as MOG, ENPP2, MYRF, ANLN, MAG and PLP1, which have been implicated in the development of AD and other neurodegenerative diseases. This integrative network biology study systematically identifies molecular signatures and networks underlying brain regional vulnerability to aging in males and females. The findings pave the way for understanding the molecular mechanisms of gender differences in developing neurodegenerative diseases such as AD.
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影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
2.5
作者：
Kato T;Konishi Y;Shimohama S;Beach TG;Akatsu H;Tooyama I
通讯作者：
Tooyama I
影响因子：
2.4
作者：
Arslan-Ergul A;Adams MM
通讯作者：
Adams MM
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
6.1
作者：
Dickson, TC;Chuckowree, JA;Vickers, JC
通讯作者：
Vickers, JC