Hippocampal disruptions of synaptic and astrocyte metabolism are primary events of early amyloid pathology in the 5xFAD mouse model of Alzheimer's disease.
Hippocampal disruptions of synaptic and astrocyte metabolism are primary events of early amyloid pathology in the 5xFAD mouse model of Alzheimer's disease.
复制标题
DOI：
10.1038/s41419-021-04237-y
复制
发表时间：
2021-10-16
影响因子：
9
通讯作者：
Waagepetersen HS
中科院分区：
文献类型：
--
作者：
Andersen JV;Skotte NH;Christensen SK;Polli FS;Shabani M;Markussen KH;Haukedal H;Westi EW;Diaz-delCastillo M;Sun RC;Kohlmeier KA;Schousboe A;Gentry MS;Tanila H;Freude KK;Aldana BI;Mann M;Waagepetersen HS
Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, this crucial metabolic interplay during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in the 5xFAD hippocampus. This hyperactive neuronal phenotype coincided with decreased hippocampal tricarboxylic acid (TCA) cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity and decreased glutamine synthesis led to hampered neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, the cerebral cortex of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism, which may suggest a metabolic compensation in this brain region. We found limited changes when we explored the brain proteome and metabolome of the 5xFAD mice, supporting that the functional metabolic disturbances between neurons and astrocytes are early primary events in AD pathology. In addition, synaptic mitochondrial and glycolytic function was selectively impaired in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex regional and cell-specific metabolic adaptations in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunctions in AD.
登录
查看更多内容
影响因子：
16.2
作者：
Bai, Bing;Wang, Xusheng;Peng, Junmin
通讯作者：
Peng, Junmin
DOI：
10.1073/pnas.1206171109
发表时间：
2012-05-29
影响因子：
11.1
作者：
Busche, Marc Aurel;Chen, Xiaowei;Konnerth, Arthur
通讯作者：
Konnerth, Arthur
影响因子：
4.2
作者：
Andersen, Jens Velde;McNair, Laura Frendrup;Waagepetersen, Helle Sonderby
通讯作者：
Waagepetersen, Helle Sonderby
影响因子：
4.2
作者：
Andersen, Jens V.;Jakobsen, Emil;Aldana, Blanca I.
通讯作者：
Aldana, Blanca I.
基础大脑代谢可能会调节Abeta在轻度认知障碍中的认知作用：大脑储备的一个例子。
DOI：
10.1523/jneurosci.3669-09.2009
发表时间：
2009-11-25
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Cohen AD;Price JC;Weissfeld LA;James J;Rosario BL;Bi W;Nebes RD;Saxton JA;Snitz BE;Aizenstein HA;Wolk DA;Dekosky ST;Mathis CA;Klunk WE
通讯作者：
Klunk WE