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Injected Amyloid Beta in the Olfactory Bulb Transfers to Other Brain Regions via Neural Connections in Mice

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Abstract

Alzheimer’s disease (AD) is characterized by progressive neuronal degeneration and pathological accumulation of amyloid plaques in the brain. It has been proposed that the prion-like spreading of amyloid beta (Aβ) protein could contribute to the progression of the disease. Olfactory bulb (OB) is one of the earliest brain regions affected in AD and olfaction is easily impaired prior to cognitive symptoms. However, it remains unclear whether Aβ accumulation in the OB would spread along olfactory projections to other connected brain regions and trigger further neurodegeneration. In the present study, we experimentally injected recombinant human Aβ1–42 (monomers and oligomers, respectively) into the mouse OB and tracked the spreading of Aβ to connected brain regions over 3 days. The results showed that both Aβ monomers and oligomers were rapidly and readily transferred from the injection site to interconnected brain regions in a neural connection manner and triggered neuronal apoptosis in the affected brain regions. Oligomeric Aβ1–42 spread more efficiently and induced more neuronal apoptosis in the affected brain regions compared to monomeric Aβ1–42. Therefore, the study provides evidence that Aβ peptides can transfer via neural connections and the pattern of Aβ peptide spreading provides understanding to manage AD.

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Acknowledgements

This study was supported by Science and Technology Program of Guangzhou, 2014J4500031, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, 2014B030301035, Macao Science and Technology Development Fund (063/2015/A2), and MYRG2016-00184-ICMS-QRCM.

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Authors and Affiliations

  1. Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, and Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital Sun Yat-Sen University, Guangzhou, 510080, China

    Baixuan He, Minying Zheng, Simei Long, Xilin Lu, Zhong Pei & Xiaoli Yao

  2. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China

    Qiang Liu, Zhe Shi & Huanxing Su

  3. School of Psychology, Nanjing Normal University, Nanjing, China

    Ti-Fei Yuan

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  1. Baixuan He
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  2. Minying Zheng
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  3. Qiang Liu
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  4. Zhe Shi
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  6. Xilin Lu
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  10. Xiaoli Yao
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Correspondence to Huanxing Su or Xiaoli Yao.

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All experimental procedures were performed in accordance with prevailing laws on animal experiments and were approved by the animal research ethical committee of Sun Yat-Sen University.

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Fig. S1

Transfer of Aβ to other brain regions at 3 h after injection into the OB. a: Representative images showing that Aβ is localized in the soma of neurons in both the ipsilateral and contralateral frontal cortex (ipsi/contra FC) of the monomeric and oligomeric animals as revealed by immunostaining NeuN staining (green) and huAβ staining (red). b: Representative images showing that huAβ-positive cells were detected in the ventral pallidum (VP) in the animals injected with Aβ oligomers, whereas no huAβ-positive cells were found in the animals injected with Aβ monomers. Scale bars: 60 μm (GIF 88 kb)

High Resolution Image (TIFF 1742 kb)

Fig. S2

DAB staining confirmed the transfer of Aβ1–42 to other brain structures at 3 h after injection into the OB. Representative images illustrating the presence of huAβ-positive cells in various brain structures such as ipsi/contra FC, PC, SSp, and Stri at 3 h after the injection of monomeric (left column) and oligomeric Aβ (middle column) into the OB. On the contrary, none of the brain structures mentioned above exhibited huAβ-positive cells when we injected monomeric Aβ into the subarachnoid space (right column). Scale bars: 100 μm (GIF 113 kb)

High Resolution Image (TIFF 2565 kb)

Fig. S3

Transfer of Aβ to other brain regions at 24 h after injection into the OB. a: Representative images showing that Aβ is localized in the soma of neurons in both the ipsilateral and contralateral piriform cortex (ipsi/contra PC) of the monomeric and oligomeric animals as revealed by immunostaining NeuN staining (green) and huAβ staining (red). b: Representative images showing that Aβ is localized in the soma of neurons in both the ipsilateral and contralateral primary somatosensory area (ipsi/contra SSp) of the monomeric and oligomeric animals as revealed by immunostaining NeuN staining (green) and huAβ staining (red). c: Representative images showing that huAβ-positive cells were detected in both the septohippocampal nucleus (ipsi/contra SHi) in the animals injected with Aβ oligomers, whereas no huAβ-positive cells were found in the animals injected with Aβ monomers. Scale bars: 60 μm (GIF 81 kb)

High Resolution Image (TIFF 1845 kb)

Fig. S4

Transfer of Aβ to other brain regions at 72 h after injection into the OB. a: Representative images showing that Aβ is localized in the soma of neurons in the ipsilateral frontal cortex (ipsi/contra FC) of the monomeric and oligomeric animals as revealed by immunostaining NeuN staining (green) and huAβ staining (red). b: Representative images showing that huAβ-positive cells were detected in the ipsilateral piriform cortex (ipsi PC) in the animals injected with Aβ oligomers, whereas no huAβ-positive cells were found in the animals injected with Aβ monomers. Scale bars: 75 μm (GIF 127 kb)

High Resolution Image (TIFF 6282 kb)

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He, B., Zheng, M., Liu, Q. et al. Injected Amyloid Beta in the Olfactory Bulb Transfers to Other Brain Regions via Neural Connections in Mice. Mol Neurobiol 55, 1703–1713 (2018). https://doi.org/10.1007/s12035-017-0446-1

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