title: Clearance of amyloid-beta in Alzheimer's disease: shifting the action site from center to periphery.
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.
authors.affiliation: 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.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Liu
authors.forename: Ye-Ran
authors.initials: YR
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiang
authors.forename: Hua-Dong
authors.initials: HD
authors.lastname: Zhou
authors.forename: Brian
authors.initials: B
authors.lastname: Giunta
authors.forename: Noralyn B
authors.initials: NB
authors.lastname: Mañucat-Tan
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
authors.forename: Yan-Jiang
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000097:blood* / Q000276:immunology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000097:blood*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007167:Immunotherapy; D008954:Models, Biological
chemical_list: D016229:Amyloid beta-Peptides
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