PXD025240-1

PXD025240 is an original dataset announced via ProteomeXchange.

Title	Hippocampal disruptions of synaptic and astrocyte metabolism during early amyloid pathology in the 5xFAD mouse model of Alzheimer’s disease
Description	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, 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.
HostingRepository	PRIDE
AnnounceDate	2021-11-09
AnnouncementXML	Submission_2021-11-09_14:41:36.768.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Niels Henning Skotte
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-04-07 03:09:14	ID requested
⏵ 1	2021-11-09 14:41:37	announced
2	2023-11-14 08:53:42	announced	2023-11-14: Updated project metadata.

10.1038/S41419-021-04237-Y;

submitter keyword: Glucose, cerebral cortex, hippocampus, AD, brain energy metabolism, mitochondria, Seahorse, synaptosomes

Matthias Mann
contact affiliation	Max-Planck-Institute of Biochemistry
contact email	mmann@biochem.mpg.de
lab head
Niels Henning Skotte
contact affiliation	University of Copenhagen
contact email	niels.skotte@cpr.ku.dk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD025240
     1. Label: PRIDE project
     2. Name: Hippocampal disruptions of synaptic and astrocyte metabolism during early amyloid pathology in the 5xFAD mouse model of Alzheimer’s disease