PXD024538

PXD024538 is an original dataset announced via ProteomeXchange.

Title	Identification and drug-induced reversion of molecular signatures of Alzheimer´s disease onset and progression in AppNL-G-F, AppNL-F and 3xTg-AD mouse models
Description	Alzheimer´s disease (AD) is the most common form of dementia. Over fifty years of intense research have revealed many key elements of the biology of this neurodegenerative disorder. However, our understanding of the molecular bases of the disease is still incomplete, and the available medical treatments for AD are mainly symptomatic and hardly effective. Indeed, the robustness of biological systems have revealed that the modulation of a single target is unlikely to yield the desired outcome, and we should move from gene-centric to systemic therapeutic strategies. Here, we present the complete characterization of three murine models of AD at different stages of the disease (i.e. onset, progression and advanced). To identify genotype-to-phenotype relationships, we combine the cognitive assessment of these mice with histological analyses and a full transcriptional and protein quantification profiling from hippocampus. Comparison between the gene and protein expression trends observed in AD progression and physiological ageing exposed certain commonalities, such as the upregulation of microglial and inflammation markers. However, although there is an accelerated ageing in AD models, there are other factors specifically associated with Aβ pathology. Despite the clear correlation between mRNA and protein levels of the dysregulated genes, we discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable. Indeed, we show that at least two of these proteins, namely lfit3 and Syt11, co-localize with Aβ plaques in the brain. Finally, we derive specific Aβ-related molecular AD signatures, and we look for drugs able to globally revert them. We found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing Aβ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels.
HostingRepository	PRIDE
AnnounceDate	2021-10-12
AnnouncementXML	Submission_2021-10-11_23:40:10.788.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marina Gay
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iTRAQ8plex-116 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-04 22:48:12	ID requested
⏵ 1	2021-10-11 23:40:11	announced

Dataset with its publication pending

submitter keyword: Alzheimer’s disease, transcriptomics, proteomics, data-driven drug discovery, in vivo models.

Patrick Aloy
contact affiliation	ICREA Research Professor Structural Bioinformatics & Network Biology Institute for Research in Biomedicine (IRB Barcelona)
contact email	paloy@irbbarcelona.org
lab head
Marina Gay
contact affiliation	Institute for Research in Biomedicine
contact email	marina.gay@irbbarcelona.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024538
     1. Label: PRIDE project
     2. Name: Identification and drug-induced reversion of molecular signatures of Alzheimer´s disease onset and progression in AppNL-G-F, AppNL-F and 3xTg-AD mouse models