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Salvianolic acid B ameliorates retinal deficits in an early-stage Alzheimer’s disease mouse model through downregulating BACE1 and Aβ generation

Acta Pharmacologica Sinica volume 44, pages 2151–2168 (2023)Cite this article

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease with subtle onset, early diagnosis remains challenging. Accumulating evidence suggests that the emergence of retinal damage in AD precedes cognitive impairment, and may serve as a critical indicator for early diagnosis and disease progression. Salvianolic acid B (Sal B), a bioactive compound isolated from the traditional Chinese medicinal herb Salvia miltiorrhiza, has been shown promise in treating neurodegenerative diseases, such as AD and Parkinson’s disease. In this study we investigated the therapeutic effects of Sal B on retinopathy in early-stage AD. One-month-old transgenic mice carrying five familial AD mutations (5×FAD) were treated with Sal B (20 mg·kg−1·d−1, i.g.) for 3 months. At the end of treatment, retinal function and structure were assessed, cognitive function was evaluated in Morris water maze test. We showed that 4-month-old 5×FAD mice displayed distinct structural and functional deficits in the retinas, which were significantly ameliorated by Sal B treatment. In contrast, untreated, 4-month-old 5×FAD mice did not exhibit cognitive impairment compared to wild-type mice. In SH-SY5Y-APP751 cells, we demonstrated that Sal B (10 μM) significantly decreased BACE1 expression and sorting into the Golgi apparatus, thereby reducing Aβ generation by inhibiting the β-cleavage of APP. Moreover, we found that Sal B effectively attenuated microglial activation and the associated inflammatory cytokine release induced by Aβ plaque deposition in the retinas of 5×FAD mice. Taken together, our results demonstrate that functional impairments in the retina occur before cognitive decline, suggesting that the retina is a valuable reference for early diagnosis of AD. Sal B ameliorates retinal deficits by regulating APP processing and Aβ generation in early AD, which is a potential therapeutic intervention for early AD treatment.

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Fig. 1: Sal B restored the function of the retina in 4-month-old 5×FAD mice.
Fig. 2: Learning and memory impairment were not detected in 4-month-old 5×FAD mice.
Fig. 3: No detectable LTP deficit in the Schaffer collateral (SC)-CA1 pathway was observed in 4-month-old 5×FAD mice hippocampus.
Fig. 4: Sal B restored the impairment of retinal structure in 4-month-old 5×FAD mice.
Fig. 5: Sal B reduced BACE1 expression and ameliorated Aβ deposition.
Fig. 6: Sal B mitigates Aβ deposition via BACE1 inhibition.
Fig. 7: Molecular dynamics models predict a stable binding of Sal B and BACE1.
Fig. 8: Sal B inhibited the sorting of BACE1 into the Golgi apparatus.
Fig. 9: Sal B inhibited microglial activation in 5×FAD mice.
Fig. 10: Sal B reduced retinal inflammation in 5×FAD mice.
Fig. 11: Sal B restored RGC deficits in 5×FAD mice.

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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

The work was supported by the National Natural Science Foundation of China (82274301 and 81774377), the Natural Science Foundation of Fujian Province of China (Grant No. 2021J01019), the National Key Research and Development Program of China (2016YFC1305903) and the Program for New Century Excellent Talents in University of China (NCET-13-0505) (to LW).

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  1. These authors contributed equally: Meng-dan Wang, Shuo Zhang

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen, 361102, China

    Meng-dan Wang, Shuo Zhang, Xing-yang Liu, Pan-pan Wang, Yi-fan Zhu, Jun-rong Zhu, Chong-shan Lv & Lei Wen

  2. Xiamen Key Laboratory for TCM Dampness Disease, Neurology & Immunology Research, Department of Traditional Chinese Medicine, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen, 361102, China

    Meng-dan Wang, Shuo Zhang, Xing-yang Liu, Pan-pan Wang, Yi-fan Zhu, Jun-rong Zhu, Chong-shan Lv & Lei Wen

  3. Eye Institute of Xiamen University, Department of Ophthalmology, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen, 361102, China

    Shi-ying Li

  4. Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China

    Sui-feng Liu

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Contributions

LW conceived the study and designed the experiments; MDW and SZ wrote the manuscript; LW, SYL, and SFL edited the manuscript; MDW and SZ performed most of the experiments; MDW, SZ, XYL, and PPW performed morphological analyses; YFZ, JRZ, CSL, SY, and SFL analyzed and contributed reagents/materials/analysis tools. XYL performed LTP analyses; LW supervised the project. All authors reviewed the manuscript.

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Correspondence to Shi-ying Li, Sui-feng Liu or Lei Wen.

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Wang, Md., Zhang, S., Liu, Xy. et al. Salvianolic acid B ameliorates retinal deficits in an early-stage Alzheimer’s disease mouse model through downregulating BACE1 and Aβ generation. Acta Pharmacol Sin 44, 2151–2168 (2023). https://doi.org/10.1038/s41401-023-01125-3

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