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PXD025240-1

PXD025240 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleHippocampal disruptions of synaptic and astrocyte metabolism during early amyloid pathology in the 5xFAD mouse model of Alzheimer’s disease
DescriptionAlzheimer’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, how this metabolic interplay may be affected 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 hippocampal brain slices of 5xFAD mice. This hyperactive neuronal phenotype coincided with decreased hippocampal TCA cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity led to decreased glutamine synthesis, in turn hampering neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, cerebral cortical slices of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism suggesting a metabolic compensation. When we explored the brain proteome and metabolome of the 5xFAD mice, we found limited changes, supporting that the functional metabolic disturbances between neurons and astrocytes are early events in AD pathology. In addition, we show that synaptic mitochondrial and glycolytic function was impaired selectively 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 region and cell specific metabolic adaptations, in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunction in AD.
HostingRepositoryPRIDE
AnnounceDate2021-11-09
AnnouncementXMLSubmission_2021-11-09_14:41:36.768.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterNiels Henning Skotte
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListNo PTMs are included in the dataset
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-04-07 03:09:14ID requested
12021-11-09 14:41:37announced
22023-11-14 08:53:42announced2023-11-14: Updated project metadata.
Publication List
10.1038/S41419-021-04237-Y;
Keyword List
submitter keyword: Glucose, cerebral cortex, hippocampus, AD, brain energy metabolism, mitochondria, Seahorse, synaptosomes
Contact List
Matthias Mann
contact affiliationMax-Planck-Institute of Biochemistry
contact emailmmann@biochem.mpg.de
lab head
Niels Henning Skotte
contact affiliationUniversity of Copenhagen
contact emailniels.skotte@cpr.ku.dk
dataset submitter
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Dataset FTP location
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