Clearance of Amyloid-Beta in Alzheimer’s Disease: Shifting the Action Site from Center to Periphery
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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.
KeywordAlzheimer’s disease Amyloid-beta Immunotherapy Adverse effects Peripheral clearance
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.
Conflict of Interest
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