Loss of Brain-Derived Estrogen Is Associated With Sex- and Age-Dependent Alterations in Memory, Affective Behavior, and Hippocampal Extracellular Matrix Gene Expression.
Overview
- Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine Northwestern University Chicago Illinois USA
- Department of Psychiatry & Behavioral Sciences, Feinberg School of Medicine Northwestern University Chicago Illinois USA
Abstract
Nearly two‐thirds of Americans with Alzheimer's disease (AD) are women. Prior research suggested that women with AD have lower brain estrogen levels than those without AD. However, how estrogen deficiency modulates this sex‐based difference in AD vulnerability is not well understood. Aromatase, the key enzyme for estrogen biosynthesis, is expressed in both neurons and astrocytes of the brain, including the hippocampus. This study aims to assess the mechanistic link between brain‐selective aromatase deficiency and sex‐specific AD vulnerability. To achieve this goal, we used brain‐specific aromatase knockout (bArKO) and whole‐body total aromatase knockout (tArKO) mice of both sexes at young (6‐ to 8‐month‐old) and old (> 19‐month‐old) ages. We found that aromatase deletion decreased brain estrogen levels in bArKO mice and circulating and brain estrogen levels in tArKO mice. Impairment in spatial working memory and social interaction behavior was observed only in old female bArKO and tArKO mice. Both young and old female, but not male, tArKO mice displayed depression‐like behavior. Bulk RNA‐seq analysis of hippocampal tissues from young and old bArKO mice of both sexes revealed enrichment of extracellular matrix‐related pathways and upregulated mRNA and/
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
The paper links to its data, not to its authors' code: see the Data section.
Tracing map
A tracing map links a paper to the code its authors published: this paper has none, so it has no map.
Data
Data links
- ncbi.nlm.nih.gov/
geo , NCBI; found in “Data Availability Statement”
Data Availability Statement
The bulk RNA‐seq data from this study have been deposited in the NCBI Gene Expression Omnibus (GEO) database under the accession number GSE285197 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 6 keywords, 13 MeSH terms, 1 funder, 122 references, 1 RRID.
Cite
This paper
Piehl, N. C., Halle, A. W., Rodriguez, G., Locci, A., Kujawa, S., Haywood, C., Coon, J., McNally, R. P., Karim, Z. A., You, T., Dong, H., Bulun, S. E., & Zhao, H. (2026). Loss of Brain-Derived Estrogen Is Associated With Sex- and Age-Dependent Alterations in Memory, Affective Behavior, and Hippocampal Extracellular Matrix Gene Expression. Aging cell, 25(6), e70551. https://
BibTeX
@article{piehl2026loss,
author = {Piehl, Natalie C. and Halle, Ariel W. and Rodriguez, Guadalupe and Locci, Andrea and Kujawa, Stacy and Haywood, Caroline and Coon, John and McNally, Ross P. and Karim, Zaina A. and You, Tianming and Dong, Hongxin and Bulun, Serdar E. and Zhao, Hong},
title = {{Loss of Brain-Derived Estrogen Is Associated With Sex- and Age-Dependent Alterations in Memory, Affective Behavior, and Hippocampal Extracellular Matrix Gene Expression}},
journal = {Aging cell},
year = {2026},
month = jun,
volume = {25},
number = {6},
pages = {e70551},
publisher = {Wiley},
issn = {1474-9718},
doi = {10.1111/
url = {https://
pmid = {42186917},
pmcid = {PMC13239850}
}
RIS
TY - JOUR
AU - Piehl, Natalie C.
AU - Halle, Ariel W.
AU - Rodriguez, Guadalupe
AU - Locci, Andrea
AU - Kujawa, Stacy
AU - Haywood, Caroline
AU - Coon, John
AU - McNally, Ross P.
AU - Karim, Zaina A.
AU - You, Tianming
AU - Dong, Hongxin
AU - Bulun, Serdar E.
AU - Zhao, Hong
TI - Loss of Brain-Derived Estrogen Is Associated With Sex- and Age-Dependent Alterations in Memory, Affective Behavior, and Hippocampal Extracellular Matrix Gene Expression
T2 - Aging cell
J2 - Aging Cell
PY - 2026
DA - 2026/
VL - 25
IS - 6
SP - e70551
SN - 1474-9718
PB - Wiley
DO - 10.1111/
UR - https://
LA - en
ER -
CSL-JSON
{
"id": "10.1111/
"type": "article-journal",
"title": "Loss of Brain-Derived Estrogen Is Associated With Sex- and Age-Dependent Alterations in Memory, Affective Behavior, and Hippocampal Extracellular Matrix Gene Expression",
"container-title": "Aging cell",
"author": [
{
"family": "Piehl",
"given": "Natalie C."
},
{
"family": "Halle",
"given": "Ariel W."
},
{
"family": "Rodriguez",
"given": "Guadalupe"
},
{
"family": "Locci",
"given": "Andrea"
},
{
"family": "Kujawa",
"given": "Stacy"
},
{
"family": "Haywood",
"given": "Caroline"
},
{
"family": "Coon",
"given": "John"
},
{
"family": "McNally",
"given": "Ross P."
},
{
"family": "Karim",
"given": "Zaina A."
},
{
"family": "You",
"given": "Tianming"
},
{
"family": "Dong",
"given": "Hongxin"
},
{
"family": "Bulun",
"given": "Serdar E."
},
{
"family": "Zhao",
"given": "Hong"
}
],
"container-title-short":
"volume": "25",
"issue": "6",
"page": "e70551",
"DOI": "10.1111/
"PMID": "42186917",
"PMCID": "PMC13239850",
"ISSN": "1474-9718",
"publisher": "Wiley",
"URL": "https://
"language": "en",
"issued": {
"date-parts": [
[
2026,
6,
1
]
]
}
}
Similar papers
The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.
- [1] doi:10.1186/s12974-026-03970-5
- Estrogen deprivation exacerbates Alzheimer's disease pathology through neuronal CTSS signaling.Journal: Journal of neuroinflammationIn common: Alzheimer's / dementia, mouse, cellular / molecular, 4 references
- [2] doi:10.1186/s40478-026-02332-9
- ATM-kinase deficiency triggers early multi-compartment remodeling of the cerebellar microenvironment.Journal: Acta neuropathologica communicationsIn common: mouse, cellular / molecular, 3 references
- [3] doi:10.1016/j.isci.2026.116188 [code]
- Genetic inactivation of Translin/
Trax RNase disrupts miRNAs, hippocampal synaptic plasticity, and memory. Journal: iScienceIn common: mouse, cellular / molecular, 3 references - [4] doi:10.3389/fneur.2026.1793970 [code]
- The cumulative impact of seizures: the science underlying how seizures beget seizures.Journal: Frontiers in neurologyIn common: 3 references
- [5] doi:10.3390/ijms27177542
- Assessment of the Association of Periodontitis and Diabetes Mellitus with Alzheimer's Disease in a Mouse Model.Journal: International journal of molecular sciencesIn common: Alzheimer's / dementia, mouse, cellular / molecular, 2 references
- [6] doi:10.1093/brain/awag080 [code]
- Early glymphatic failure in AppNL-F knock-in mice is linked to parenchymal border macrophages loss.Journal: Brain : a journal of neurologyIn common: Alzheimer's / dementia, mouse, cellular / molecular, 2 references
- [7] doi:10.1038/s41593-026-02367-0 [code]
- A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.Journal: Nature neuroscienceIn common: Alzheimer's / dementia, cellular / molecular, 2 references
- [8] doi:10.1186/s12974-026-03888-y
- Integrated imaging and molecular profiling reveals APOE4-associated neurovascular and glial disruptions in young adult mice.Journal: Journal of neuroinflammationIn common: Alzheimer's / dementia, mouse, cellular / molecular, 2 references
- [9] doi:10.1002/exp2.70160
- &
lt;i& gt;RBFOX1& lt;/ i& gt; Dysfunction Unlocks & lt;i& gt;APOE4& lt;/ i& gt;-Associated Microglial Genesis and Exacerbates Alzheimer's Pathology in Human Cerebral Organoids. Journal: Exploration (Beijing, China)In common: Alzheimer's / dementia, cellular / molecular, 2 references - [10] doi: [code]
- Diffusion-relaxation MRI as virtual histology: separable microstructural signatures of AD pathology in ex vivo human brainJournal: Research squareIn common: Alzheimer's / dementia, cellular / molecular, 2 references
Contribute
The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.
Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.
Claim this paper
Correct its record
Say what each link of this record is, remove the ones that are not the paper's, add the ones that are missing. The correction becomes a new version of the record, in its Versions section.
Request its removal
To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).
Discussion, reproductions, activity
Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.
Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.
Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.