Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons
Open accessAbstract
Convergent evidence has revealed an association between insulin resistance and Alzheimer's disease (AD), and the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, rosiglitazone, an insulin sensitizer and mitochondrial activator, improves cognition in patients with early or mild-to-moderate AD. Apolipoprotein (apo) E4, a major genetic risk factor for AD, exerts neuropathological effects through multiple pathways, including impairment of dendritic spine structure and mitochondrial function. Here we show that rosiglitazone significantly increased dendritic spine density in a dose-dependent manner in cultured primary cortical rat neurons. This effect was abolished by the PPAR-γ-specific antagonist, GW9662, suggesting that rosiglitazone exerts this effect by activating the PPAR-γ pathway. Furthermore, the C-terminal-truncated fragment of apoE4 significantly decreased dendritic spine density. Rosiglitazone rescued this detrimental effect. Thus, rosiglitazone might improve cognition in AD patients by increasing dendritic spine density.
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In neurons, apoE4 is associated with decreased neurite outgrowth.
“decreased neurite outgrowth”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [34]
The Results report that apoE4 reduced dendritic spine density in primary cortical neurons compared with apoE3. The introduction mentions neurite outgrowth, but our copy does not clearly state that apoE4 decreases it; spine density and neurite outgrowth are distinct measures. No page number is available in the indexed passages. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn neurons, apoE4 is associated with impaired mitochondrial respiration.
“In neurons, apoE4 is associated with impaired mitochondrial respiration”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [34]
The introduction (page unavailable) says that apoE4 fragments in neurons impair mitochondrial membrane potential and function, and the Results likewise describe impaired mitochondrial function. The copy does not specifically identify impaired mitochondrial respiration, so it supports the broader association but not that particular measure. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn neurons, apoE4 is associated with neurotoxicity.
“and neurotoxicity [10, 17–19, 34, 35]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [34]
Apolipoprotein E4 decreases spine density both in vivo and in vitro.
“apolipoprotein (apo) E4–a major genetic risk factor for Alzheimer's disease–decreases spine density both in vivo [18], [19] and in vitro [20], [21]”
From Arf4 Determines Dentate Gyrus-Mediated Pattern Separation by Regulating Dendritic Spine Development (2012) · cites this paper as [20]
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Arf4 Determines Dentate Gyrus-Mediated Pattern Separation by Regulating Dendritic Spine Development
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- Authors
- Brodbeck, J., Balestra, M. E., Saunders, A. M., Roses, A. D., Mahley, R. W., & Huang, Y.
- Affiliations
- Gladstone Institutes (US)
- GlaxoSmithKline (United States) (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-01-29
- Volume
- 105
- Issue
- 4
- Pages
- 1343-1346
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2234140
- OpenAlex
- W2015540884
- Cited by
- 86
- References
- 8
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 6 · 2015: 5 · 2014: 7 · 2013: 6 · 2012: 7
- FWCI
- 8.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- GlaxoSmithKline
- Gladstone Institutes
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- rosiglitazone, dendritic spine density, APOE ε4, PPARγ, Alzheimer's disease, cortical neurons, insulin resistance, mitochondrial function, GW9662, cognitive impairment, synaptic plasticity
- MeSH terms
- Rosiglitazone, Animals, Animals, Newborn, Cell Count, Cells, Cultured, Cerebral Cortex, Dendrites, Neurons, Thiazolidinediones, Dendritic Spines, Rats, Apolipoprotein E4
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