PXD066415

PXD066415 is an original dataset announced via ProteomeXchange.

Title	Targeted and partial in vivo reprogramming of hippocampal neurons restores memory loss and neural synchrony in a mouse model of Alzheimer’s disease
Description	Alzheimer’s disease (AD) is the most common neurodegenerative disorder with a huge impact on society due to its prevalence. Major risk factor to develop AD is aging. Indeed, most of the physiopathological events described in AD are also hallmarks of accelerated aging. To counteract accelerated aging, a new technology based on partial reprogramming using the Yamanaka’s factors (YFs) has emerged. We previously showed that a tight control of YFs in hippocampal principal neurons was safe and induced substantial cognitive improvements in the 5xFAD mouse model of AD. However, the exact mechanisms by which in vivo partial and intermittent reprogramming improves AD-related phenotypes are poorly understood. Here we tested whether YFs targeted and intermittent expression in hippocampal neurons can improve the AD-related phenotypes of the P301S model, and we explored through which mechanisms are being mediated such improvements. First, we observed that tight expression of YFs in pyramidal neurons of the CA1 increases the frequency of excitatory postsynaptic currents in brain slices and that YFs induction also increased neural synchrony and firing frequency in GCaMP6-expressing hippocampal neural networks. Next, we induced intermittent and targeted YFs expression in principal hippocampal neurons of adult control (i4F) and P301S transgenic mice for 6 months. Such YFs expression improved several phenotypes in P301S mice that depended on sex. Concomitant with the behavioral recovery, Tau pathology was reduced, and some epigenetic markers were restored. Additionally, neuroinflammation was also ameliorated. Deepen on potential underling molecular mechanisms of these improvements we observed that the N-methyl-D-aspartate receptors (NMDARs) multiprotein macro-complexes including several subunits and risk factors for AD such as PYK2 (Ptk2b) were restored in reprogrammed P301S mice. Finally, impaired neural synchrony in P301S mice was also rescued upon reprogramming. In conclusion we show for the first time a relevant improvement in cognitive and emotional P301S mice behavioral phenotypes due to targeted and partial reprogramming using YFs. We also describe the potential molecular underlying mechanism involving the NMDAR receptor macro-complexes composition and signaling.
HostingRepository	jPOST
AnnounceDate	2026-07-22
AnnouncementXML	Submission_2026-07-21_08:00:10.560.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joaquin Fernandez-Irigoyen
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	S-carboxamidomethyl-L-cysteine; N6-acetyl-L-lysine; 2-pyrrolidone-5-carboxylic acid (Gln); L-methionine sulfoxide
Instrument	instrument

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-22 06:14:42	ID requested
⏵ 1	2026-07-21 08:00:11	announced

Dataset with its publication pending

submitter keyword: Targeted and partial in vivo reprogramming of hippocampal neurons restores memory loss and neural synchrony in a mouse model of Alzheimer’s disease

Albert Giralt
lab head
Joaquin Fernandez-Irigoyen
contact affiliation	Navarrabiomed
dataset submitter

jPOST dataset URI

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