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Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer's disease.

Overview

Authors: Tatsuki Nakagawa1,2, Jiayun L. Xie1, Kiwon Park1,3, Kai Cao1, Marjan Savadkohighodjanaki1, Yutian J. Zhang1, Heechul Jun1, Ayana Ichii1, Jason Y. Lee1, Shogo Soma1,4, Yasmeen K. Medhat1, Takaomi C. Saido5, Kei M. Igarashi1,2,3,6,7,8
ORCID iDs: Tatsuki Nakagawa, Kiwon Park, Kai Cao, Heechul Jun, Jason Y. Lee, Shogo Soma, Takaomi C. Saido, Kei M. Igarashi
  1. Department of Anatomy and Neurobiology, School of Medicine, University of California,Irvine, CA USA
  2. Cognitive Physiology Lab, Graduate School of Medicine, Tohoku University,Sendai, Japan
  3. Department of Biomedical Engineering, Samueli School of Engineering, University of California,Irvine, CA USA
  4. Present Address: Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine,Kyoto, Japan
  5. Lab for Proteolytic Neuroscience, RIKEN Center for Brain Science,Wako, Japan
  6. Center for Neural Circuit Mapping, School of Medicine, University of California,Irvine, CA USA
  7. Center for the Neurobiology of Learning and Memory, University of California,Irvine, CA USA
  8. Institute for Memory Impairments and Neurological Disorders, University of California,Irvine, CA USA
Institutions: University of California, Irvine (United States); Tohoku University (Japan); Kyoto Prefectural University of Medicine (Japan); RIKEN Center for Brain Science (Japan)
Journal: Nature neuroscience, volume 29, issue 6, pages 1386-1396
Dates: received 13 September 2024; accepted 6 March 2026; published online 23 April 2026; in print 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41593-026-02260-w · PMID 42026254 · PMCID PMC13246448 · OpenAlex W7155381817
Open access: hybrid, a free copy (OpenAlex)
Status: code verified
Categories: human (organism), mouse (organism), Alzheimer's / dementia (population), Parkinson's (population)
Methods: Connectivity, Statistics, Smoothing, state filtering, decompositions, Preprocessing, Evoked potentials, Single-unit activity, calcium imaging, Machine learning
Keywords: Alzheimer's disease, Cortex
MeSH: Alzheimer Disease*, Dopamine*, Dopaminergic Neurons*, Entorhinal Cortex*, Amyloid beta-Protein Precursor, Animals, Disease Models, Animal, Gene Knock-In Techniques, Humans, Levodopa, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic (* major topic)
Topic: Alzheimer's disease research and treatments (Physiology, Medicine), according to OpenAlex
Funding: BrightFocus Foundation (BrightFocus) (A2019380S, A2022018F); Brain Research Foundation (BRFSG-2017-04); MEXT | Japan Science and Technology Agency (JST) (JPMJPR2481); Alzheimer’s Association (AARF-22-923955)
Citations: cited by 2 papers (Europe PMC); 41 references in the paper

Abstract

The entorhinal cortex is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer’s disease (AD). The entorhinal cortex therefore has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. Here we show that dopamine neurons projecting their axons to the lateral entorhinal cortex (LEC), critical for memory formation in healthy brains, become dysfunctional from the early pathological stage and cause associative memory impairments in amyloid precursor protein knock-in mice. Dopamine dysfunction led to the disruption of associative memory encoding of LEC layer 2/3. Optogenetic reactivation of LEC dopamine fibers rescued associative learning behavior. L-DOPA treatment restored memory encoding of LEC neurons and associative memory of amyloid precursor protein knock-in mice. These results suggest early dysfunction of LEC-projecting dopamine neurons underlie memory impairment in AD from early stages, pointing to a need for clinical investigation of LEC dopamine in patients with AD.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

No file of the authors' code could be read here: it is described below, and read at its source.

igarashilab.org/resource

License: none: the authors keep all their rights
State: the link answers, verified on 29 September 2026
Evidence: the link answers
Software Heritage: not checked
Found in: “Code availability”
Not found: README, license file, CITATION.cff, environment file, tests, continuous integration, documentation
Availability: 1 check, the latest on 29 September 2026: the link answers (HTTP 200)
  • 29 September 2026: the link answers (HTTP 200)
At the source: igarashilab.org/resource

Code availability

We used standard functions in MATLAB and no special functions were developed. Analytical codes are available at https://www.igarashilab.org/resource.

Reproduced under the paper's license (CC BY), from the paper cited above.

Tracing map

Proposed by the machine: these links were found in the paper and verified at the source, without human review. The map will receive a Zenodo DOI once one of the paper's authors has validated it with their ORCID.

What the map holds:

  • 1 repository of the authors' code, each at its verified commit, with its license and how the link was found in the paper;
  • 0 scripts, each with its path and the digest of its content;
  • no match between paragraphs and code yet;
  • neither the text of the paper nor the code itself.

Its JSON (tracing-map.json) is deposited on Zenodo with its DOI once the map is validated.

Data

Datasets cited

Data availability

Neurophysiological data are available at https://www.igarashilab.org/resource.

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, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 2 keywords, 14 MeSH terms, 4 funders, 40 references.

Cite

This paper

Nakagawa, T., Xie, J. L., Park, K., Cao, K., Savadkohighodjanaki, M., Zhang, Y. J., Jun, H., Ichii, A., Lee, J. Y., Soma, S., Medhat, Y. K., Saido, T. C., & Igarashi, K. M. (2026). Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer's disease. Nature neuroscience, 29(6), 1386-1396. https://doi.org/10.1038/s41593-026-02260-w

BibTeX

@article{nakagawa2026early,
author = {Nakagawa, Tatsuki and Xie, Jiayun L. and Park, Kiwon and Cao, Kai and Savadkohighodjanaki, Marjan and Zhang, Yutian J. and Jun, Heechul and Ichii, Ayana and Lee, Jason Y. and Soma, Shogo and Medhat, Yasmeen K. and Saido, Takaomi C. and Igarashi, Kei M.},
title = {{Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer's disease}},
journal = {Nature neuroscience},
year = {2026},
month = apr,
volume = {29},
number = {6},
pages = {1386--1396},
publisher = {Nature Portfolio},
issn = {1097-6256},
doi = {10.1038/s41593-026-02260-w},
url = {https://doi.org/10.1038/s41593-026-02260-w},
pmid = {42026254},
pmcid = {PMC13246448}
}

RIS

TY - JOUR
AU - Nakagawa, Tatsuki
AU - Xie, Jiayun L.
AU - Park, Kiwon
AU - Cao, Kai
AU - Savadkohighodjanaki, Marjan
AU - Zhang, Yutian J.
AU - Jun, Heechul
AU - Ichii, Ayana
AU - Lee, Jason Y.
AU - Soma, Shogo
AU - Medhat, Yasmeen K.
AU - Saido, Takaomi C.
AU - Igarashi, Kei M.
TI - Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer's disease
T2 - Nature neuroscience
J2 - Nat Neurosci
PY - 2026
DA - 2026/04/23
VL - 29
IS - 6
SP - 1386
EP - 1396
SN - 1097-6256
PB - Nature Portfolio
DO - 10.1038/s41593-026-02260-w
UR - https://doi.org/10.1038/s41593-026-02260-w
LA - en
ER -

CSL-JSON

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