Passive Immunotherapies Targeting Amyloid Beta and Tau Oligomers in Alzheimer’s Disease

Abstract

Keywords:amyloid beta tau Alzheimer's disease protein oligomers passive immunotherapy protein aggregation protein structure blood brain barrier clearance CNS a b s t r a c t Alzheimer's disease (AD) is historically difficult to treat, in part because of the inaccessible nature of brain pathology. Amyloid beta and tau proteins drive pathology by forming toxic oligomers that eventually deposit as insoluble amyloid plaques and neurofibrillary tangles. Recent clinical studies suggest that effective drugs must specifically target oligomers, not native monomers or insoluble fibrils. Passive immunotherapy is a promising pharmaceutical strategy used to specifically target these oligomers in situ. Using the specificity of antibodies coupled with the natural power of the body's immune response, this treatment provides an opportunity for safe clearance of pathogenic protein species from the brain. Passive immunotherapies against amyloid beta and tau oligomers have progressed to clinical trials, with many currently in progress. Biochemical studies of antibody-oligomer complexes have helped identify previously unknown toxic epitopes, thus providing knowledge to the AD field as a whole. This minireview focuses on the efforts to develop passive immunotherapy treatments for AD and discusses the knowledge gained from recent failures and clinical trials in progress.

RETRACTED: The Iron Chelator Deferiprone Improves the Phenotype in a Mouse Model of Tauopathy1

“…neurodegeneration is still unknown, a number of studies report that the aberrant activation of tau kinases and MAPT mutations appear to be the most probable reasons for tau dysregulation [8][9][10][11]. However, numerous tau/tau kinase-targeting therapies have been developed with little to moderate efficacy in clinical trials [12], which may suggest that other pathways may be involved in these disorders. Indeed, the metal hypothesis is an emerging area of research in this field which suggests that transition metals (in particular iron) may play a mechanistic and therapeutic role in neurodegenerative disorders.…”

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

“…The monoclonal antibodies are collected and given to a patient with AD. Their own immune system then clears the antigens bound to the antibodies 984 . A big problem for this approach is that few immunoglobulins dosed into blood will enter the brain.…”

“…The peripheral sink hypothesis holds that Aβ can slowly leave the brain, down a concentration gradient, if it is mopped up in the blood 985 . Alternatively, passive immunisation may work by antibodies crossing the BBB, activating microglia and triggering phagocytosis of antibody-bound antigens, perhaps using strategies to facilitate this process 984 .…”

Passive Immunization With a Novel Monoclonal Anti-PrP Antibody TW1 in an Alzheimer’s Mouse Model With Tau Pathology

“…Tau pathology targeted immunotherapy is a less explored area of investigation compared to Aβ targeted approaches; however, it is a very active area of study with two trials of active immunization and ten on-going passive immunization trials (Götz and Götz, 2019;Plotkin and Cashman, 2020;Soeda and Takashima, 2020;Vander Zanden and Chi, 2020). An important criterion for this approach is that the immune response generated must avoid interacting with native, monomeric tau in neurons; hence, the majority of the anti-tau antibodies being tested are more specific to aggregated, oligomeric tau species (Plotkin and Cashman, 2020;Soeda and Takashima, 2020;Vander Zanden and Chi, 2020). These anti-tau antibodies aim to mainly act in the extracellular space, to stop the prion-like spread of tau oligomer pathology.…”