Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice
Open accessAbstract
A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five-month-old male and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7-month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (Abeta) and numbers of Abeta immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model suggests that such drugs administered prophylactically might retard the development of AD in humans.
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Chronic administration of selective serotonin reuptake inhibitors (SSRIs) reduces brain Aβ levels in mice.
“chronic administration of selective serotonin reuptake inhibitors (SSRIs) reduces brain Aβ levels in mice (17–19).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [18]
The Results report that five months of paroxetine treatment reduced cortical Aβ1−40 levels in male and female 3xTgAD mice. The same section reports no significant effect on Aβ1−42; the study tested paroxetine, not SSRIs as a class. The claim therefore omits important limits on which Aβ level fell and which drug was studied. (LLM, conf=0.88)
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- Authors
- NELSON, R., GUO, Z., HALAGAPPA, V, PEARSON, M., GRAY, A., MATSUOKA, Y., BROWN, M., MARTIN, B., IYUN, T., & MAUDSLEY, S.
- Affiliations
- Meharry Medical College (US)
- National Institute on Aging (US)
- Georgetown University (US)
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2007-05
- Volume
- 205
- Issue
- 1
- Pages
- 166-176
- ISSN
- 0014-4886 (ISSN-L)
- PMC
- PMC1979096
- OpenAlex
- W2114092053
- Cited by
- 173
- References
- 108
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 6 · 2023: 9 · 2022: 9 · 2021: 8 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 11 · 2016: 10 · 2015: 10 · 2014: 12 · 2013: 11 · 2012: 16
- FWCI
- 7.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (Z01AG000312, AG022455, Z01AG000317, K01AG022455)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- paroxetine, Alzheimer's disease, 3xTg-AD mice, amyloid-beta, tau pathology, cognitive impairment, spatial navigation, hippocampus, amygdala, sex differences, depression as risk factor, behavioral deficits
- MeSH terms
- Alzheimer Disease, Amygdala, Animals, Avoidance Learning, Behavior, Animal, Mental Disorders, Cerebral Cortex, Disease Models, Animal, Female, Hippocampus, Male, Mice, Transgenic, Motor Activity, Peptide Fragments, Swimming, Amyloid beta-Peptides, Selective Serotonin Reuptake Inhibitors, Paroxetine, Maze Learning, Tauopathies, Mice
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