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
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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.
KeywordsAβ Alzheimer’s disease Immunotherapy Tau Tauopathy
We are thankful to Ms. Janet Murphy for secretarial assistance. Studies described in this publication were supported by the New York State Office of People with Developmental Disabilities (OPWDD). Tau antibodies 43D and 77E9 employed for this study were generated and characterized under the supervision of Dr. Inge Grundke-Iqbal who passed away on September 22, 2012.
Conflict of interest
The authors declare no conflict of interest.
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