Immunotherapy for Alzheimer's disease.
The amyloid cascade hypothesis states that overproduction of amyloid-beta peptide (Abeta/AbetaP) or failure to clear this peptide, leads to Alzheimer's disease (AD) primarily through amyloid deposition, presumed to be involved in neurofibrillary tangle formation; these lesions are then associated with cell death which is reflected in memory impairment, the hallmarks of this dementia. The abundant evidence that Abeta aggregation/oligomerization is an essential early event in AD pathogenesis has prompted intensive search for therapeutics that target various conformations of Abeta. Several labs have bred AD diseased models of transgenic mice that produce human Abeta and develop plaques and neuron damage in their brains as well as immunological aspects of the disease pathogenesis. The immune system appears to participate in AD pathogenesis. There is evidence for partial tolerance against Abeta in mutant amyloid precursor protein (APP) transgenic mice as well as in AD patients. Animal models of the disease enabled the immunological concept for treatment of conformational diseases to gain more attention and immunization approaches are being pursued in order to stimulate clearance of brain amyloid plaques. In spite of the first clinical setback, this research field has clearly strengthened the hypothesis that Abeta plays a central role in AD and has stimulated a new area for development of Alzheimer's therapeutics. The renewed human phase clinical trials toward improved immunotherapeutic strategies which maintain the beneficial effects without adverse side effects are under further evaluation.
Solomon
Beka
B
Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel. beka@post.tau.ac.il
Frenkel
Dan
D
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D007167:Immunotherapy / Q000379:methods*; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D014611:Vaccination / Q000379:methods