Immunological Approaches for Amyloid-beta Clearance Toward Treatment for Alzheimer's Disease

摘要

The pathology of Alzheimer’s disease is characterized primarily by extracellular plaques andnintracellular neurofibrillary tangles. Plaques are composed mainly of the amyloid-beta peptide,nwhereas tangles are derived from the cytoskeletal protein tau. The most studied hypothesisnof development of the disease is that of the amyloid cascade, which states that overproductionnof amyloid-beta peptide, or failure to clear this peptide, leads to Alzheimer’sndisease primarily through amyloid deposition, which is presumed to be involved in neurofibrillaryntangle formation; these lesions are then associated with cell death, which is reflectednin memory impairment, the hallmarks of this dementia. We developed a new conceptnshowing that site-directed antibodies against amyloid-beta peptide may modulate formationnof amyloid filaments, which has become the theoretical basis of the immunological approachnfor treatment of Alzheimer’s disease. The performance of anti-beta-amyloid antibodies inntransgenic mouse models of Alzheimer’s disease showed they are delivered to the central nervousnsystem, clearing amyloid plaques and protecting the mice from learning and age-relatednmemory deficits. Amyloid plaque clearance via specific anti-amyloid-beta peptide antibodiesnfollows multiple mechanisms. As immunotherapy is at the crossroads of immunology andnthe nervous system, a deeper understanding of the amyloid-beta peptide clearance mechanismnmay lead to an optimized therapeutic approach to the treatment of Alzheimer’s disease.nAntibodies generated with the first-generation vaccine might not have the desired therapeuticnproperties to target the “correct” mechanism, however, new immunological approaches arennow under consideration.