Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies

Abstract

Intraneuronal accumulation of abnormally hyperphosphorylated tau in the brain is a histopathological hallmark of Alzheimer's disease and a family of related neurodegenerative disorders collectively called tauopathies. At present there is no effective treatment available for these progressive neurodegenerative diseases which are clinically characterized by dementia in mid to old-age. Here we report the treatment of 14-17-months-old 3xTg-AD mice with tau antibodies 43D (tau 6-18) and 77E9 (tau 184-195) to the N-terminal projection domain of tau or mouse IgG as a control by intraperitoneal injection once a week for 4 weeks, and the effects of the passive immunization on reduction of hyperphosphorylated tau, Aβ accumulation and cognitive performance in these animals. We found that treatment with tau antibodies 43D and 77E9 reduced total tau level, decreased tau hyperphosphorylated at Ser199, Ser202/Thr205 (AT8), Thr205, Ser262/356 (12E8), and Ser396/404 (PHF-1) sites, and a trend to reduce Aβ pathology. Most importantly, targeting N-terminal tau especially by 43D (tau 6-18) improved reference memory in the Morris water maze task in 3xTg-AD mice. We did not observe any abnormality in general physical characteristics of the treated animals with either of the two antibodies during the course of this study. Taken together, our studies demonstrate for the first time (1) that passive immunization targeting normal tau can effectively clear the hyperphosphorylated protein and possibly reduce Aβ pathology from the brain and (2) that targeting N-terminal projection domain of tau containing amino acid 6-18 is especially beneficial. Thus, targeting selective epitopes of N-terminal domain of tau may present a novel effective therapeutic opportunity for Alzheimer disease and other tauopathies.

Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer’s Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aβ Antibody and by mGluR5 Blockade

“…Immunohistochemical studies for evaluation of human APP/Aβ expression were performed on free-floating brain sections, as described previously (Kazim et al, 2014; Chohan et al, 2015; Dai et al, 2015). Every 8–9th brain section was chosen for densitometric quantification which was carried out using a minimum of five brain sections/mouse from five to six animals/group.…”

Tau passive immunization inhibits not only tau but also Aβ pathology

“…Active immunization with tau phosphopeptides reduces tau pathology [16–22] and rescues or slows cognitive decline in rodents [16, 19, 21, 22]. Passive immunotherapy using antibodies against tau has also been shown to slow disease progression [19, 23–28]. …”

“…In a previous study, we discovered that passive immunization with tau antibody to the N-terminal domain of tau not only reduced tau pathology but also showed a trend toward ameliorating Aβ pathology in triple-transgenic (3×Tg)-AD mice at moderate to severe stages of the disease [28]. In the present study, we administrated tau antibodies by intravenous injection into 3×Tg-AD mice at a mild stage of the pathology (12 months old) once weekly for up to 6 weeks; 3×Tg-AD mice start developing Aβ plaques at approximately 9 months and tau pathology starts at approximately 12 months [42–44].…”

Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

“…Targeting numerous other epitopes has been shown to be effective in several studies. These include non-phosphorylated- [27,30,32,41,42,46–48,69,70], phosphorylated- [20,24,25,27,29,35,39,43,49], conformational-/oligomeric [20,31,33,34,40,44,45], and a truncated epitope [66,71]. Since these studies have various designs, they cannot be easily compared to identify the best epitopes to target.…”