PXD040310

PXD040310 is an original dataset announced via ProteomeXchange.

Title	Subcellular proteomics and iPSC modeling uncover mechanisms of axonal pathology in Alzheimer’s disease
Description	Amyloid deposits in Alzheimer’s disease (AD) are surrounded by large numbers of plaque-associated axonal spheroids (PAAS). PAAS disrupt axonal electrical conduction and neuronal network function and correlate with AD severity. However, the mechanisms of their formation remain largely unknown. To address this, we developed a proximity labeling approach to uncover the PAAS proteomes in human AD postmortem brains and mice. Proteomics analysis highlighted the activation of protein turnover, cytoskeleton dynamics and lipid transport. The PI3K/AKT/mTOR signaling, a master regulator of these biological processes, is also activated and expressed in PAAS, and strongly correlated with disease severity in AD humans. Using human iPSC modeling and Cre/lox mice, we found that mTOR inhibition markedly reduced PAAS formation in humans and mice. Together, we assembled a multidisciplinary toolkit and uncovered novel mechanisms of axonal spheroid pathology. This pipeline can be applied to examine new targets for axonal pathology in AD and neurodegeneration.
HostingRepository	PRIDE
AnnounceDate	2025-02-20
AnnouncementXML	Submission_2025-02-20_12:59:48.329.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yifei Cai
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-21 02:45:38	ID requested
⏵ 1	2025-02-20 12:59:48	announced

10.1038/S43587-025-00823-3;

submitter keyword: AD mice,proximity labeling proteomics, human postmortem brain, axonal spheroid pathology

Jaime Grutzendler
contact affiliation	Department of Neurology and Neuroscience Yale University
contact email	jaime.grutzendler@yale.edu
lab head
Yifei Cai
contact affiliation	Yale University
contact email	yifeicaichina@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/02/PXD040310

PRIDE project URI

• PRIDE
  1. PXD040310
     1. Label: PRIDE project
     2. Name: Subcellular proteomics and iPSC modeling uncover mechanisms of axonal pathology in Alzheimer’s disease