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Clearance of Amyloid-Beta in Alzheimer’s Disease: Shifting the Action Site from Center to Periphery

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Abstract

Amyloid-beta (Aβ) is suggested to play a causal role in the pathogenesis of Alzheimer’s disease (AD). Immunotherapies are among the most promising Aβ-targeting therapeutic strategies for AD. But, to date, all clinical trials of this modality have not been successful including Aβ vaccination (AN1792), anti-Aβ antibodies (bapineuzumab, solanezumab and ponezumab), and intravenous immunoglobulin (IVIG). We propose that one reason for the failures of these clinical trials may be the adverse effects of targeting the central clearance of amyloid plaques. The potential adverse effects include enhanced neurotoxicity related to Aβ oligomerization from plaques, neuroinflammation related to opsonized Aβ phagocytosis, autoimmunity related to cross-binding of antibodies to amyloid precursor protein (APP) on the neuron membrane, and antibody-mediated vascular and neuroskeletal damage. Overall, the majority of the adverse effects seen in clinical trials were associated with the entry of antibodies into the brain. Finally, we propose that peripheral Aβ clearance would be effective and safe for future Aβ-targeting therapies.

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Acknowledgment

This work was supported by the National Natural Science Foundation of China (grant no. 81270423 and 30973144) and the Natural Science Foundation Project of CQCSTC (grant no. CSTC2010BA5004). The authors thank N. Wei at Daping Hospital of Third Military Medical University for assistance with creating the figures and Ms Kate Rees from University of South Australia for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital and Institute of Field Surgery, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong district, Chongqing, China

    Yu-Hui Liu, Ye-Ran Wang, Yang Xiang, Hua-Dong Zhou & Yan-Jiang Wang

  2. Neuroimmunology Laboratory, and Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, 3515 E. Fletcher Ave., MDT 14, Tampa, FL, 33613, USA

    Brian Giunta & Jun Tan

  3. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia

    Noralyn B. Mañucat-Tan & Xin-Fu Zhou

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  1. Yu-Hui Liu
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  2. Ye-Ran Wang
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  4. Hua-Dong Zhou
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  9. Yan-Jiang Wang
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Correspondence to Yan-Jiang Wang.

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Liu, YH., Wang, YR., Xiang, Y. et al. Clearance of Amyloid-Beta in Alzheimer’s Disease: Shifting the Action Site from Center to Periphery. Mol Neurobiol 51, 1–7 (2015). https://doi.org/10.1007/s12035-014-8694-9

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  • DOI: https://doi.org/10.1007/s12035-014-8694-9

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