Cognitive decline, Aβ pathology, and blood–brain barrier function in aged 5xFAD mice
Issued Date
2024-12-01
Resource Type
eISSN
20458118
Scopus ID
2-s2.0-85188738116
Journal Title
Fluids and Barriers of the CNS
Volume
21
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Fluids and Barriers of the CNS Vol.21 No.1 (2024)
Suggested Citation
Nehra G., Promsan S., Yubolphan R., Chumboatong W., Vivithanaporn P., Maloney B.J., Lungkaphin A., Bauer B., Hartz A.M.S. Cognitive decline, Aβ pathology, and blood–brain barrier function in aged 5xFAD mice. Fluids and Barriers of the CNS Vol.21 No.1 (2024). doi:10.1186/s12987-024-00531-x Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/97805
Title
Cognitive decline, Aβ pathology, and blood–brain barrier function in aged 5xFAD mice
Corresponding Author(s)
Other Contributor(s)
Abstract
Background: Patients with Alzheimer's disease (AD) develop blood–brain barrier dysfunction to varying degrees. How aging impacts Aβ pathology, blood–brain barrier function, and cognitive decline in AD remains largely unknown. In this study, we used 5xFAD mice to investigate changes in Aβ levels, barrier function, and cognitive decline over time. Methods: 5xFAD and wild-type (WT) mice were aged between 9.5 and 15.5 months and tested for spatial learning and reference memory with the Morris Water Maze (MWM). After behavior testing, mice were implanted with acute cranial windows and intravenously injected with fluorescent-labeled dextrans to assess their in vivo distribution in the brain by two-photon microscopy. Images were processed and segmented to obtain intravascular intensity, extravascular intensity, and vessel diameters as a measure of barrier integrity. Mice were sacrificed after in vivo imaging to isolate brain and plasma for measuring Aβ levels. The effect of age and genotype were evaluated for each assay using generalized or cumulative-linked logistic mixed-level modeling and model selection by Akaike Information Criterion (AICc). Pairwise comparisons were used to identify outcome differences between the two groups. Results: 5xFAD mice displayed spatial memory deficits compared to age-matched WT mice in the MWM assay, which worsened with age. Memory impairment was evident in 5xFAD mice by 2–threefold higher escape latencies, twofold greater cumulative distances until they reach the platform, and twice as frequent use of repetitive search strategies in the pool when compared with age-matched WT mice. Presence of the rd1 allele worsened MWM performance in 5xFAD mice at all ages but did not alter the rate of learning or probe trial outcomes. 9.5-month-old 15.5-month-old 5xFAD mice had twofold higher brain Aβ40 and Aβ42 levels (p < 0.001) and 2.5-fold higher (p = 0.007) plasma Aβ40 levels compared to 9.5-month-old 5xFAD mice. Image analysis showed that vessel diameters and intra- and extravascular dextran intensities were not significantly different in 9.5- and 15.5-month-old 5xFAD mice compared to age-matched WT mice. Conclusion: 5xFAD mice continue to develop spatial memory deficits and increased Aβ brain levels while aging. Given in vivo MP imaging limitations, further investigation with smaller molecular weight markers combined with advanced imaging techniques would be needed to reliably assess subtle differences in barrier integrity in aged mice.