Immunotherapy for Alzheimer's disease

被引:74
|
作者
Wisniewski, Thomas [1 ,2 ,3 ]
Goni, Fernando [1 ]
机构
[1] NYU, Dept Neurol, Sch Med, Alexandria ERSP, New York, NY 10016 USA
[2] NYU, Dept Pathol, Sch Med, Alexandria ERSP, New York, NY 10016 USA
[3] NYU, Dept Psychiat, Sch Med, Alexandria ERSP, New York, NY 10016 USA
关键词
Amyloid beta; Tau; Vaccination; Immunomodulation; Alzheimer's disease; Transgenic mice; AMYLOID-BETA-PEPTIDE; ANTI-TAU ANTIBODIES; REDUCES A-BETA; MOUSE MODEL; PASSIVE-IMMUNIZATION; INTRAVENOUS IMMUNOGLOBULIN; NEUROFIBRILLARY TANGLES; HYPERPHOSPHORYLATED-TAU; COGNITIVE DECLINE; FIBRIL FORMATION;
D O I
10.1016/j.bcp.2013.12.020
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD the normal soluble amyloid 13 (sA beta) peptide is converted into oligomeric/fibrillar A beta. The oligomeric forms of A beta are thought to be the most toxic, while fibrillar A beta becomes deposited as amyloid plaques and congophilic angiopathy, which serve as neuropathological markers of the disease. In addition the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat AD. Among the more exciting and advanced of these approaches is vaccination. Active and passive Immunotherapy targeting only A beta has been successful in many AD model animal trials; however, the more limited human data has shown much less benefit so far, with encephalitis occurring in a minority of patients treated with active immunization and vasogenic edema or amyloid-related imaging abnormalities (ARIA) being a complication in some passive immunization trials. Therapeutic intervention targeting only tau has been tested only in mouse models; and no approaches targeting both pathologies concurrently has been attempted, until very recently. The immune approaches tried so far were targeting a self-protein, albeit in an abnormal conformation; however, effective enhanced clearance of the disease associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation. The design of future more effective immunomodulatory approaches will need to target all aspects of AD pathology, as well as specifically targeting pathological oligomeric conformers, without the use of any self-antigen. (C) 2014 Elsevier Inc. All rights reserved.
引用
收藏
页码:499 / 507
页数:9
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