Restoring metabolism of myeloid cells reverses cognitive decline in ageing.
Restoring metabolism of myeloid cells reverses cognitive decline in ageing.
复制标题
恢复骨髓细胞的代谢逆转衰老中的认知能力下降。
DOI：
10.1038/s41586-020-03160-0
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发表时间：
2021-03
期刊：
影响因子：
64.8
通讯作者：
Andreasson KI
中科院分区：
文献类型：
--
作者：
Minhas PS;Latif-Hernandez A;McReynolds MR;Durairaj AS;Wang Q;Rubin A;Joshi AU;He JQ;Gauba E;Liu L;Wang C;Linde M;Sugiura Y;Moon PK;Majeti R;Suematsu M;Mochly-Rosen D;Weissman IL;Longo FM;Rabinowitz JD;Andreasson KI
衰老的特点是持续的促炎反应的发展，导致动脉粥样硬化、代谢综合征、癌症和虚弱。衰老的大脑也容易受到炎症的影响，与年龄相关的认知能力下降和阿尔茨海默病的高患病率就证明了这一点。从系统上讲，循环的促炎因子可以促进认知能力下降，在大脑中，小胶质细胞失去清除与神经变性相关的错误折叠蛋白质的能力。然而，随着年龄的增长，引发和维持不适应炎症的潜在机制尚不清楚。在这里，我们发现衰老小鼠骨髓细胞的生物能量受到抑制，以响应脂质信使前列腺素E2（PGE2）信号的增加，PGE2是炎症的主要调节剂。在衰老的巨噬细胞和小胶质细胞中，pge2通过其EP2受体发出信号，促进葡萄糖转化为糖原，减少葡萄糖通量和线粒体呼吸。这种能量不足的状态会导致不适应的促炎反应，而衰老的骨髓细胞对葡萄糖作为主要燃料来源的依赖进一步增强了这种状态。在老年小鼠中，抑制髓系EP2信号可以使细胞生物能量、全身和脑炎症状态、海马突触可塑性和空间记忆恢复活力。此外，阻断外周髓系EP2信号传导足以恢复老年小鼠的认知能力。我们的研究表明，认知衰老不是一个静态的或不可逆转的条件，而是可以通过重新编程骨髓糖代谢来恢复年轻的免疫功能来逆转的。
Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty, –. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer’s disease, –. Systemically, circulating pro-inflammatory factors can promote cognitive decline,, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration,. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2(PGE2), a major modulator of inflammation. In ageing macrophages and microglia, PGE2signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.
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影响因子：
44.1
作者：
通讯作者：
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影响因子：
29
作者：
Lampropoulou V;Sergushichev A;Bambouskova M;Nair S;Vincent EE;Loginicheva E;Cervantes-Barragan L;Ma X;Huang SC;Griss T;Weinheimer CJ;Khader S;Randolph GJ;Pearce EJ;Jones RG;Diwan A;Diamond MS;Artyomov MN
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Artyomov MN
影响因子：
15.9
作者：
Johansson, Jenny U.;Woodling, Nathaniel S.;Andreasson, Katrin I.
通讯作者：
Andreasson, Katrin I.
影响因子：
7.3
作者：
Fox, Brian M.;Beck, Hilary P.;Olson, Steven H.
通讯作者：
Olson, Steven H.
影响因子：
3.7
作者：
Attar A;Liu T;Chan WT;Hayes J;Nejad M;Lei K;Bitan G
通讯作者：
Bitan G