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Origins of Beta Amyloid Differ Between Vascular Amyloid Deposition and Parenchymal Amyloid Plaques in the Spinal Cord of a Mouse Model of Alzheimer’s Disease

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Abstract

Cerebral amyloid angiopathy (CAA) refers to pathological changes occurring in cerebral blood vessels caused by deposition of beta amyloid (Aβ) protein. However, the mechanisms involved in the origin of Aβ for the formation of CAA and its link to parenchymal amyloid depositions remained to be unraveled. Here, we found CAA and parenchymal plaques distributed separately instead of mingling with each other in the spinal cord of TgCRND8 mice. Parenchymal plaques predominantly located in the dorsal horn whereas CAA distributed in the ventral horn. We further found that the ratio of Aβ40/Aβ42 was significantly higher in the ventral than that in the dorsal by ELISA assay, suggesting that origin of Aβ forming parenchymal plaques may be different from that of CAA in the spinal cord. This hypothesis was further demonstrated by the surgical methods which indicated eliminating parenchymal plaques did not alter CAA in the affected spinal cord. We also examined the ratio of Aβ40/Aβ42 in the cerebral spinal fluid (CSF) in order to identify the origin of the CAA formation, and found the Aβ40/Aβ42 ratio was similar to that of CAA formation in the ventral horn. We further demonstrated that CSF tracer distributed along ventral horn vessels, in exactly the same pattern as Aβ deposition in CAA in ventral part of spinal cord. These findings verified the concept that CSF influx may act as a constant source for delivering Aβ, and contribute to the growth of paraarterial deposits in CAA. Taken together, the results of the present study highlight the important role of the Aβ40/Aβ42 ratio in determining vascular versus parenchymal amyloid deposition. Unlike parenchymal plaques, Aβ of CAA comes from CSF; thus, manipulation of CSF Aβ could represent a novel strategy to treat CAA.

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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgments

We would like to thank Yin Mei Wong for her technical assistance.

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Authors and Affiliations

  1. School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong

    Qiuju Yuan, Yan-Fang Xian, Ying Tang, Juntao Zou, Xie Zhang, Pengyun Huang & Zhi-Xiu Lin

  2. Brain Research Centre, School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China

    Qiuju Yuan, Yan-Fang Xian & Zhi-Xiu Lin

  3. Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong

    Xiaodong Liu

  4. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Sha Tin, Hong Kong

    Wutian Wu & You-qiang Song

  5. GHM Institute of CNS Regeneration, Jinan University, Guangzhou, China

    Wutian Wu

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Electronic Supplementary Material

Supplementary Fig 1.

Characterization of Aβ pathology in the brain of aged TgCRND8 mice. A: The ratio of Aβ40/Aβ42 in the forebrain and CSF of aged TgCRND8 mice at the age of 18 months (n = 4). The level of Aβ40 of Aβ42 was measured by ELISA. Quantitative analysis revealed that ratio of Aβ40/Aβ42 was around 0.43, indicating the Aβ favors the formation for parenchymal plaques. The ratio of Aβ40/Aβ42 in CSF was much higher than that in the mouse forebrain. B and C: Aβ pathology in the brain revealed by Aβ (red) (B) and thioflavin S (green) (C) staining. Predominant parenchymal plaques were observed in the forebrain (thin arrows in B and C). In contrast, very limited CAA was seen in this region (thick arrow in B and C). D: Quantitative analysis for the mean area fraction of parenchymal plaques and CAA revealed parenchymal plaques are predominant Aβ pathology in the forebrain of TgCRND8 mice. * significantly different (p < 0.01) compared with the parenchymal plaques. Scale bar, 100 μm. (PNG 106 kb)

High resolution image (TIF 18691 kb)

Supplementary Fig 2.

Blood vessel diameter in the ventral part is larger than that in the dorsal part of the spinal cord. Blood vessel diameters were measured in horizontal sections of cervical cord stained with lectin in the non-TgCRND8 mice at the age of 3 months (n = 5). The smallest distance across individual blood vessel was defined as the diameter of the blood vessel and was measured in NIH Image 1.6 software. Forty vessels in either the dorsal or ventral part of the spinal cord were measured in each animal. A: the dorsal part of the spinal cord. B: the ventral part of the spinal cord. Quantitative analysis revealed blood vessel diameter in the ventral part was significantly larger than that in the dorsal part. * significantly different (p < 0.001) compared with the dorsal part. Scale bar, 100 μm. (PNG 32 kb)

High resolution image (TIF 2792 kb)

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Yuan, Q., Liu, X., Xian, YF. et al. Origins of Beta Amyloid Differ Between Vascular Amyloid Deposition and Parenchymal Amyloid Plaques in the Spinal Cord of a Mouse Model of Alzheimer’s Disease. Mol Neurobiol 57, 278–289 (2020). https://doi.org/10.1007/s12035-019-01697-4

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