Anti-amyloid-beta to tau-based immunization: developments in immunotherapy for Alzheimer's disease

Abstract

Immunotherapy might provide an effective treatment for Alzheimer disease (AD). A unique feature of AD immunotherapies is that an immune response against a self antigen needs to be elicited without causing adverse autoimmune reactions. Current research is focussed on two possible targets in this regard: One is the inhibition of accumulation and deposition of Amyloid beta 1-42 (Aβ42), which is one of the major peptides found in senile plaques and the second target is hyperphosphorylated tau, which forms neurofibrillary tangles inside the nerve cell and shows association with the progression of dementia. Mouse models have shown that immunotherapy targeting Aβ42 as well as tau with the respective anti-Aβ or anti-tau antibodies can provide significant improvements in these mice. While anti-Aβ immunotherapy (active and passive immunizations) is already in several stages of clinical trials, tau based immunizations have been analyzed only in mouse models. Recently, as a significant correlation of progression of dementia and levels of phoshorylated tau was found, high interest has again focussed on further development of tau based therapies. While Aβ immunotherapy might delay the onset of AD, immunotherapy targeting tau might provide benefits in later stages of this disease. And last but not least, targeting Aβ and tau simultaneously with immunotherapy might provide additional therapeutic effects as these two pathologies are likely synergistic; an approach which has not been tested yet. In this review, we will summarize animal models used to test possible therapies for AD, some of the facts about Aβ42 and tau biology, present on overview on halted, ongoing and upcoming clinical trials together with ongoing preclinical studies targeting tau or Aβ42.

A noninflammatory immune response in aged DNA Aβ42-immunized mice supports its safety for possible use as immunotherapy in AD patients

“…Results from mice receiving passive Aβ immunization had shown that anti-Aβ antibodies enter the brain and are found in regions with high amyloid concentrations; the ability to enter the brain changes with age and might depend also on features specific to the antibodies (Banks et al, 2007; Bard et al, 2000). The antibody amounts found in aged DNA-immunized mice (mean 53 μg/mL plasma) were higher than the antibody levels, we had found earlier in transgenic APP mice (2.9 μg/mL plasma) and inwhich we found a substantial reduction in plaque load (50%) and total Aβ42 levels (41%) in brain from the immunized mice compared with control mice (Lambracht-Washington and Rosenberg, 2013b; Qu et al, 2006, 2007). …”

Sporadic inclusion-body myositis: A degenerative muscle disease associated with aging, impaired muscle protein homeostasis and abnormal mitophagy

“…Some of the trials had to be interrupted, either because of detrimental side-effects or lack of the evident efficacy. Those studies were recently in [135,136]. Other approaches, which are also being discussed as possible treatments of AD, are a) BACE-1 inhibitors, and b) tau-immunotherapy, reviewed in [136,137].…”

“…Those studies were recently in [135,136]. Other approaches, which are also being discussed as possible treatments of AD, are a) BACE-1 inhibitors, and b) tau-immunotherapy, reviewed in [136,137]. However, their application to human patients still remains unknown.…”

T Cells—Protective or Pathogenic in Alzheimer’s Disease?

“…Passive immunization has also been assessed in clinical trials (Lambracht-Washington and Rosenberg 2013;Wilcock and Colton 2008). This can, in theory, negate the effects of immune senescence observed in elderly AD patients and avoid T cell-mediated encephalitis.…”