Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition
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Abstract
We undertook longitudinal β-amyloid positron emission tomography (Aβ-PET) imaging as a translational tool for monitoring of chronic treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone in Aβ model mice. We thus tested the hypothesis this treatment would rescue from increases of the Aβ-PET signal while promoting spatial learning and preservation of synaptic density. Here, we investigated longitudinally for 5 months PS2APP mice ( N = 23; baseline age: 8 months) and App NL – G – F mice ( N = 37; baseline age: 5 months) using Aβ-PET. Groups of mice were treated with pioglitazone or vehicle during the follow-up interval. We tested spatial memory performance and confirmed terminal PET findings by immunohistochemical and biochemistry analyses. Surprisingly, Aβ-PET and immunohistochemistry revealed a shift toward higher fibrillary composition of Aβ-plaques during upon chronic pioglitazone treatment. Nonetheless, synaptic density and spatial learning were improved in transgenic mice with pioglitazone treatment, in association with the increased plaque fibrillarity. These translational data suggest that a shift toward higher plaque fibrillarity protects cognitive function and brain integrity. Increases in the Aβ-PET signal upon immunomodulatory treatments targeting Aβ aggregation can thus be protective.
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Methylene blue and peroxisome proliferator-activated receptor gamma agonists have been reported to have conformation-altering, toxicity-modifying effects similar to those observed after Inpp5d knockdown.
“Methylene blue59 and peroxisome proliferator-activated receptor gamma agonists60 have been reported to have similar conformation-altering, toxicity-modifying effects.”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [60]
The inability to associate altered pathology with detectable changes in brain function may be a result of the focus on the earliest stages of pathology and/or a dissociation between plaque load and function.
“which may be a result of our focus on the earliest stages of pathology and/or a dissociation between plaque load and function, which has been observed in other settings.21,60,62”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [60]
Increased plaque compaction may be a protective mechanism.
“Increased plaque compaction may be a protective mechanism,59,60”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [60]
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Castranio, E. L., Hasel, P., Haure‐Mirande, J., Ramirez Jimenez, A. V., Hamilton, B. W., Kim, R. D., Glabe, C. G., Wang, M., Zhang, B., Gandy, S., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12821 · Cited by 74 · see citing works
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Self-citation
- Authors
- Blume, T., Deussing, M., Biechele, G., Peters, F., Zott, B., Schmidt, C., Franzmeier, N., Wind, K., Eckenweber, F., Sacher, C., Shi, Y., Ochs, K., Kleinberger, G., Xiang, X., Focke, C., Lindner, S., Gildehaus, F.-J., Beyer, L., von Ungern-Sternberg, B., Bartenstein, P., Baumann, K., Adelsberger, H., Rominger, A., Cumming, P., Willem, M., Dorostkar, M. M., Herms, J., & Brendel, M.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Ludwig-Maximilians-Universität München (DE)
- TUM Klinikum (DE)
- Institut für Schlaganfall- und Demenzforschung (DE)
- F. Hoffmann-La Roche AG (CH)
- University Hospital of Bern (CH)
- Queensland University of Technology (AU)
- Corresponding author
- Brendel, Matthias
- ORCID
- Venue
- Frontiers in Aging Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2022-03-30
- Volume
- 14
- Pages
- 854031-854031
- ISSN
- 1663-4365 (ISSN-L)
- PMC
- PMC9007038
- OpenAlex
- W4220753439
- Cited by
- 10
- References
- 15
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 1
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Aging Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, cc-by)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (RO5194/1-1, BR4580/1-1)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- PPARγ agonists, pioglitazone, amyloid-beta, amyloid plaques, spatial learning, synaptic density, cognitive function, Alzheimer's disease, APP transgenic mice, immunomodulatory therapy
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