Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model
Abstract
Epidemiological studies indicate that women have a higher risk of Alzheimer's disease (AD) even after adjustment for age. Though transgenic mouse models of AD develop AD-related amyloid beta (Abeta) and/or tau pathology, gender differences have not been well documented in these models. In this study, we found that female 3xTg-AD transgenic mice expressing mutant APP, presenilin-1 and tau have significantly more aggressive Abeta pathology. We also found an increase in beta-secretase activity and a reduction of neprilysin in female mice compared to males; this suggests that a combination of increased Abeta production and decreased Abeta degradation may contribute to higher risk of AD in females. In contrast to significantly more aggressive Abeta pathology in females, gender did not affect the levels of phosphorylated tau in 3xTg-AD mice. These results point to the involvement of Abeta pathways in the higher risk of AD in women. In addition to comparison of pathology between genders at 9, 16 and 23 months of age, we examined the progression of Abeta pathology at additional age points; i.e., brain Abeta load, intraneuronal oligomeric Abeta distribution and plaque load, in male 3xTg-AD mice at 3, 6, 9, 12, 16, 20 and 23 months of age. These findings confirm progressive Abeta pathology in 3xTg-AD transgenic mice, and provide guidance for their use in therapeutic research.
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Only female mice were used because AD pathology development is far less pronounced and more variable in male 3xTg-AD mice.
“Only female mice were used in this study since the development of AD pathology is far less pronounced and more variable in male 3xTg-AD mice [18,19].”
From Brain microstructure abnormalities in the 3xTg-AD mouse – A diffusion MRI and morphology correlation study (2022) · cites this paper as [18]
Female mice have a greater Aβ burden.
“Female mice were used as they have a greater Aβ burden (Carroll et al., 2007, 2010a,b; Hirata-Fukae et al., 2008).”
From Early stage alterations in white matter and decreased functional interhemispheric hippocampal connectivity in the 3xTg mouse model of Alzheimer’s disease. (2019) · cites this paper as Hirata-Fukae et al., 2008
Male 3xTg-AD mice no longer consistently exhibit plaque and tangle pathology.
“Since the initial generation of the model, it has been described by multiple groups and confirmed by the donating investigator that male 3xTg-AD mice no longer consistently exhibit plaque and tangle pathology [23–25].”
These results align with published literature and reinforce the translatability of the 3xTg-AD model.
“Together, these results align with published literature [20, 21, 23, 24, 26, 27] and reinforce the translatability of the 3xTg-AD model.”
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- Authors
- Hirata-Fukae, C., Li, H.-F., Hoe, H.-S., Gray, A. J., Minami, S. S., Hamada, K., Niikura, T., Hua, F., Tsukagoshi-Nagai, H., Horikoshi-Sakuraba, Y., Mughal, M., Rebeck, G. W., LaFerla, F. M., Mattson, M. P., Iwata, N., Saido, T. C., Klein, W. L., Duff, K. E., Aisen, P. S., & Matsuoka, Y.
- Affiliations
- Georgetown University Medical Center (US)
- National Institute on Aging (US)
- University of California, Irvine (US)
- RIKEN (JP)
- Northwestern University (US)
- Columbia University (US)
- Corresponding author
- Matsuoka, Yasuji
- ORCID
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 1216
- Pages
- 92-103
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W2086333867
- Cited by
- 284
- References
- 6
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 16 · 2023: 11 · 2022: 18 · 2021: 18 · 2020: 16 · 2019: 14 · 2018: 25 · 2017: 15 · 2016: 15 · 2015: 14 · 2014: 15 · 2013: 12 · 2012: 17
- FWCI
- 12.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of California, Irvine
- National Institute on Aging (R01AG026478, AG022455, R01AG022547, K01AG022455, AG026478, R01AG029460, R01AG018877)
- 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
- Alzheimer's disease, sex differences, amyloid-beta pathology, tau phosphorylation, 3xTg-AD mice, neprilysin, amyloid plaques, amyloid-beta oligomers, disease progression, transgenic mouse model
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Brain, Female, Male, Mice, Transgenic, Sex Characteristics, Species Specificity, Amyloid beta-Peptides, tau Proteins, Mice, Presenilin-1, Amyloid Precursor Protein Secretases
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