Anti-amyloid beta to tau - based immunization: Developments in immunotherapy for Alzheimer 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.

Keywords: Alzheimer disease; Aβ42; active and passive vaccination; amyloid precursor protein; immunotherapy; neurofibrillary tangles; prevention trials; tau protein.

Figure 1

(A–E) Effective amyloid beta (Aβ) immunotherapy in an Alzheimer’s disease mouse model with active DNA Aβ42 trimer immunization. Results from two groups of DNA Aβ42 trimer-immunized APP/PS1 double transgenic mice and the respective control DNA-immunized mice are shown (n on the x-axis indicates the number of mice used in this particular experiment). Immunization was started in both groups in 4-month-old mice and was continued for eleven immunizations until the mice were 12 months old. Group A was killed for final analyses (plasma antibody levels, brain Aβ histology, and biochemistry) 14 days following the last immunization, while mice in group B were killed four months after the eleventh immunization. Anti-Aβ42 IgG antibody levels were shown in (A) for group A, and in (C and D) for group B. The comparison of plasma anti-Aβ42 levels of DNA Aβ42-immunized mice and control mice that had received DNA luciferase (Luc), immunizations showed in both groups the presence of Aβ42-specific antibodies in the DNA Aβ42-immunized mice (P = 0.0092 [A] and 0.0305 [D]). In both groups, a significant reduction of Aβ42 levels in brain was found in the DNA Aβ42-immunized mice in comparison to the respective control groups. Mice in group A showed an amyloid reduction of 60% (B), while mice in group B showed a reduction of Aβ42 brain levels of 25% (E). This difference might be due to the time differences in the two groups between final immunizations and brain level analyses, as well as the marked differences in total Aβ42 levels in brain due to the 4-month age difference between the analyses for mice in groups A and B. Symbols used in the diagrams are as follows: in (A, B, D, and E), the grey circles show values from Luc-immunized control mice, and the black circles show values from DNA Aβ42-immunized mice. In (C), the antibody levels were compared in the same mouse group (Group B) 14 days after the final immunization (divided black and white circles) and 4 months after the final immunization (black circles). For statistics (unpaired t-test with two-tailed P-values). P-values of #0.05 were considered significant. Abbreviations: APP, amyloid precursor protein; PS1, presenilin 1.

Figure 2

Common features of anti-amyloid beta (Aβ) and anti-tau antibodies. Both pathophysiological hallmarks of Alzheimer’s disease (AD) are caused by overproduction, aggregation, and misfolding of brain self-antigens. Active and passive immunotherapy and the respective anti-Aβ and anti-tau antibodies share common features of antibody actions.