OSCR

Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes.

Overview

Authors: LaShae Nicholson1,2, Si Jie Tang1,2,3, Tejaswini Karra1,2,4, Habiba Abouelatta1,2,5, Stephen M. Strittmatter1,2
ORCID iDs: Si Jie Tang
  1. Departments of Neuroscience and Neurology, Yale School of Medicine,New Haven, CT USA
  2. Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine,New Haven, CT USA
  3. Present Address: School of Medicine, University of California Davis Medical Center,Sacramento, CA USA
  4. Present Address: Institute of Neuropathology, University Medical Centre Göttingen,37077 Göttingen, Germany
  5. Present Address: Department of Neuroscience and Behavior, Mount Holyoke College,South Hadley, MA USA
Institutions: Yale University (United States); University of California Davis Medical Center (United States); Universitätsmedizin Göttingen (Germany); Mount Holyoke College (United States)
Journal: Molecular neurodegeneration, volume 21, issue 1, article 44
Dates: received 12 September 2025; accepted 6 May 2026; published online 3 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s13024-026-00946-0 · PMID 42237401 · PMCID PMC13459496 · OpenAlex W7163418346
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), mouse (organism), other condition (population), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions
Keywords: Insulin resistance, Obesity, Glucose, Diabetes, Alzheimer’s, Microglia, Inhibitory neurons, snRNA-seq
MeSH: Alzheimer Disease*, Cerebral Cortex*, Insulin Resistance*, Microglia*, Neurons*, Animals, Diet, High-Fat, Disease Models, Animal, Gene Knock-In Techniques, Humans, Mice, Mice, Transgenic, Phenotype, tau Proteins (* major topic)
Topic: Alzheimer's disease research and treatments (Physiology, Medicine), according to OpenAlex
Funding: Kavli Institute for Neuroscience, Yale School of Medicine (none); NIH (R01034924); National Institutes of Health,United States (P30AG066508)
Citations: not cited yet (Europe PMC); 83 references in the paper
Research resources: goat anti-IBA1 RRID:AB_10982846, rabbit anti-Meis2 RRID:AB_11026529, rabbit anti-PBX1 RRID:AB_11205760, guinea pig anti-Pvalb RRID:AB_2156476, mouse biotinylated AT8 RRID:AB_223648, rabbit anti-pThr217 RRID:AB_2533741, chicken anti-Synapsin½ RRID:AB_2622240, guinea pig anti-Gephyrin RRID:AB_2661777, rabbit anti-β amyloid RRID:AB_2797642, chicken anti-GFAP RRID:AB_304558, rat anti-Cd68 RRID:AB_322219, sheep anti-Trem2 RRID:AB_356109, rabbit anti-IBA1 RRID:AB_839504, rabbit anti-PSD-95 RRID:AB_87705, rabbit anti-VGAT RRID:AB_887871, rabbit anti-VGLUT1 RRID:AB_887877, rabbit anti-p(Y128)ErbB4 RRID:AB_940986, RRID:SCR_024672

Abstract

Background: Metabolic dysfunction contributes to the risk and progression of Alzheimer’s disease (AD), yet the cellular mechanisms linking impaired insulin signaling and systemic metabolic stress to brain dysfunction remain incompletely defined.

Methods: We examined the impact of chronic high-fat, high-sugar (HFHS)-induced insulin resistance on metabolic parameters, spatial learning and memory, and in vivo glial activation and neuropathology in Alzheimer’s disease knock-in mice expressing human mutant APP and wild-type (WT) tau. Single-nucleus RNA sequencing was performed to resolve cell-type-specific transcriptional responses.

Results: HFHS-diet induced weight gain, hyperglycemia, and glucose intolerance in WT and AD knock-in mice as compared to control diet-fed mice. However, impaired spatial learning was observed only in AD knock-in mice on the HFHS diet, even though there was no greater amyloid-β deposition or tau phosphorylation than in control diet AD knock-in mice. Transcriptomic profiling revealed that HFHS-fed AD mice engaged a distinct glial program, which we termed the metabolic impairment in neurodegeneration (MinD) state, characterized by upregulation of genes involved in synaptic targeting and trans-synaptic signaling shared across microglia, astrocytes, and oligodendrocytes. In parallel, we identified selective induction of the transcription factor Meis2 in cortical Layer 2 inhibitory neurons, which exhibited HFHS-diet transcriptional remodeling enriched for pathways regulating vesicle release, synaptic organization, and membrane excitability. These coordinated glial and neuronal transcriptional changes were associated with reduced inhibitory synapse density in HFHS-fed AD mice.

Conclusion: Diet-induced insulin resistance in AD knock-in mice is associated with coordinated glial and inhibitory neuron transcriptional remodeling and cognitive impairment, without alteration of the classical amyloid and tau pathology present in the AD mice fed a lean diet. These findings define cellular programs linking systemic insulin metabolic dysfunction to cortical circuity vulnerability in AD.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13024-026-00946-0.

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

Code

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Data

Datasets cited

Data availability

All data generated and/or analyzed during this study are included in this published article and its supplementary information files. The transcriptomics dataset supporting the conclusions of this article is available in the NCBI’s Gene Expression Omnibus (GEO) repository, GSE262426 at [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE262426].

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, 5 authors, 8 keywords, 14 MeSH terms, 3 funders, 81 references, 18 RRIDs.

Cite

This paper

Nicholson, L., Tang, S. J., Karra, T., Abouelatta, H., & Strittmatter, S. M. (2026). Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes. Molecular neurodegeneration, 21(1), 44. https://doi.org/10.1186/s13024-026-00946-0

BibTeX

@article{nicholson2026insulin,
author = {Nicholson, LaShae and Tang, Si Jie and Karra, Tejaswini and Abouelatta, Habiba and Strittmatter, Stephen M.},
title = {{Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes}},
journal = {Molecular neurodegeneration},
year = {2026},
month = jun,
volume = {21},
number = {1},
pages = {44},
publisher = {BMC},
issn = {1750-1326},
doi = {10.1186/s13024-026-00946-0},
url = {https://doi.org/10.1186/s13024-026-00946-0},
pmid = {42237401},
pmcid = {PMC13459496}
}

RIS

TY - JOUR
AU - Nicholson, LaShae
AU - Tang, Si Jie
AU - Karra, Tejaswini
AU - Abouelatta, Habiba
AU - Strittmatter, Stephen M.
TI - Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes
T2 - Molecular neurodegeneration
J2 - Mol Neurodegener
PY - 2026
DA - 2026/06/03
VL - 21
IS - 1
SP - 44
SN - 1750-1326
PB - BMC
DO - 10.1186/s13024-026-00946-0
UR - https://doi.org/10.1186/s13024-026-00946-0
LA - en
ER -

CSL-JSON

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