PXD044437-1

PXD044437 is an original dataset announced via ProteomeXchange.

Title	Chronic optogenetic activation of hippocampal pyramidal neurons replicates the proteome footprint of Alzheimer’s disease-like pathology
Description	Neuronal overexcitability can disrupt synapse formation and strength and elicit synaptic changes which in turn give rise to neuronal hyperactivity, and eventually overall abnormal neural circuit processing. Such network disruption impairs neuronal function and survival, resulting in the onset of neurodegeneration and Alzheimer’s disease. Yet, the sequence of synaptic changes that result from sustained neuronal hyperactivity remain elusive. To address this, we adopted an optogenetic stimulation strategy to generate a model of long-lasting neuronal hyperactivity in hippocampal pyramidal neurons. We applied this to both wild-type mice and in the 5xFAD mice presenting mutations that confer susceptibility to develop Alzheimer’s disease in humans. We analyzed the proteome changes occurring after a month of daily chronic optogenetic stimulation which surprisingly revealed shared proteomic signatures between photoactivated wild-type and 5xFAD mice. Proteins involved in translation, protein transport, autophagy, and more importantly in the Alzheimer’s disease pathology were upregulated in wild-type mice. By contrast, optogenetic overdrive in the 5xFAD mice resulted in extensive downregulation of proteins participating in mRNA processing and phosphorylation. The footprint of protein change upon driving hyperactivity in the wild-type mice included downregulation of glutamatergic and GABAergic synapse proteins indicating potential disruption of synaptic transmission. Moreover, the target of rapamycin mTORC1 signaling pathway, involved in the onset of several neuropathological disorders, was hyperactive after the optogenetic activation in wild-type mice. In turn, these proteome and signalling changes in the hippocampus of wild-type mice resulted in spatial memory loss and notably augmented Αβ42 secretion. Altogether, these findings indicate that neuronal overexcitability and hyperactivity alone replicate the footprint of proteomic changes within the hippocampus seen in mice harboring Alzheimer’s disease-linked mutations. Thus, sustained neuronal hyperactivity may contribute to synaptic transmission disruption, memory deficits and the neurodegenerative process associated with Alzheimer’s disease.
HostingRepository	PRIDE
AnnounceDate	2025-08-01
AnnouncementXML	Submission_2025-08-01_03:29:26.366.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Martina Samiotaki
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-08 02:00:29	ID requested
⏵ 1	2025-08-01 03:29:26	announced

Dataset with its publication pending

submitter keyword: Neuronal hyperactivity

Hippocampus

Optogenetics

Stable Step Function Opsin (SSFO)

Proteomics

Alzheimer’s disease

Neurodegeneration

Yves De Koninck
contact affiliation	1. CERVO Brain Research Centre, Quebec Mental Health Institute; Québec, QC, G1E 1T2, Canada. 2. Department of Psychiatry & Neuroscience, Université Laval; Québec, QC, G1V 0A6, Canada.
contact email	yves.dekoninck@neuro.ulaval.ca
lab head
Martina Samiotaki
contact affiliation	Protein Analysis Laboratory B.S.R.C. "Alexander Fleming", Alexander Fleming Street 34 16672, Vari, Greece
contact email	samiotaki@fleming.gr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD044437
     1. Label: PRIDE project
     2. Name: Chronic optogenetic activation of hippocampal pyramidal neurons replicates the proteome footprint of Alzheimer’s disease-like pathology