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Amyloid beta accumulation in TgF344-AD rats is associated with reduced cerebral capillary endothelial Kir2.1 expression and neurovascular uncoupling

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Abstract

Alzheimer’s disease (AD) exerts a tremendous socio-economic burden worldwide. Although reduced cerebral blood flow is an early and persistent symptom that precedes the loss of cognitive function in AD, the underlying molecular and cellular mechanisms remain unclear. The present study investigated whether capillary endothelial inward rectifier potassium 2 (Kir2.1) expression is reduced in TgF344-AD (AD) rats and contributes to neurovascular uncoupling and cognitive deficits in AD. Three- to fourteen-month-old AD rats expressing mutant human APP and PS1 and age-matched wild-type (WT) F344 rats were studied. AD rats exhibited higher amyloid beta (Aβ) expression in the brain as early as 3 months of age and amyloid plaques by 4 months of age. Functional hyperemic responses induced by whisker stimulation were impaired at 4 months of age, which were exacerbated in 6-month- and 14-month-old AD rats. The expression of Kir2.1 protein was significantly lower in the brains of 6-month-old AD versus WT rats, and Kir2.1 coverage was lower in the cerebral microvasculature of AD than in WT rats. Aβ1–42 reduced the Kir2.1 expression in cultured capillary endothelial cells. Cerebral parenchymal arterioles with attached capillaries exhibited a reduced vasodilator in response to 10 mM K+ applied to capillaries, and constricted less following administration of a Kir2.1 channel blocker, compared to WT vessels. These results indicate that capillary endothelial Kir2.1 expression is reduced and contributes to impaired functional hyperemia in AD rats at early ages, perhaps secondary to elevated Aβ expression.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This study was supported by grants R01 AG057842, RF1 AG079336, and HL138685 from the National Institutes of Health; 23PRE1018124 from the American Heart Association; and G20221001-3551 from Sigma Xi.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA

    Xing Fang, Jane J. Border, Patrice L. Rivers, Huawei Zhang, Jan Michael Williams & Richard J. Roman

  2. Department of Physiology, Medical College of Georgia, Augusta University, 1462 Laney Walker Blvd, Augusta, GA, 30912, USA

    Fan Fan

Authors
  1. Xing Fang
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  2. Jane J. Border
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  3. Patrice L. Rivers
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  4. Huawei Zhang
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  5. Jan Michael Williams
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  6. Fan Fan
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  7. Richard J. Roman
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Contributions

F. F., X. F., and R. J. R. conceived and designed the research project; X. F., J. B., P. R., and H. Z. performed the experiments; X. F., J. B., P. R., R. J. R., and F. F. analyzed the data; X. F., R. J. R., and F. F. interpreted the results of experiments; X. F., H. Z., and F. F. prepared the figures; X. F. and R. J. R. drafted, edited, and revised the manuscript; X. F., F. F., J. B., P. R., H. Z., R. J. R., and J. M. W. approved the final version of the manuscript.

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Correspondence to Fan Fan or Richard J. Roman.

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Fang, X., Border, J.J., Rivers, P.L. et al. Amyloid beta accumulation in TgF344-AD rats is associated with reduced cerebral capillary endothelial Kir2.1 expression and neurovascular uncoupling. GeroScience 45, 2909–2926 (2023). https://doi.org/10.1007/s11357-023-00841-2

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