Premium
O2–06–03: ACU‐193: A candidate therapeutic antibody that selectively targets soluble beta‐amyloid oligomers
Author(s) -
Krafft Grant,
Hefti Franz,
Goure William,
Jerecic Jasna,
Iverson Kent,
Walicke Patricia
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.04.166
Subject(s) - chemistry , amyloid beta , amyloid (mycology) , biodistribution , pharmacology , neurodegeneration , in vivo , immunogenicity , alzheimer's disease , biochemistry , biophysics , antibody , in vitro , peptide , medicine , biology , immunology , disease , inorganic chemistry , microbiology and biotechnology
However, the relationship between these two proteins and neuronal loss lacks amechanistic explanation. Furthermore, evidence from animal models suggests that amyloid beta toxicity is mediated by tau [1-6]. We hypothesize that tau oligomers formation plays curial role in driving AD pathogenesis. Thus, tau oligomers represent an ideal therapeutic target for the treatment of AD. In order to study the removal of toxic tau assemblies in an animal model of AD (Tg2576), we generated a tau oligomer specific antibody (TOMA). This antibody does not recognize the functional monomeric tau or oligomers from other amyloidogenic proteins. Methods: Here we used the Tg2576 mouse model which overexpress the human APP with the Swedish double mutations (K670N, M671L) under the control of a hamster prion protein promoter .14-month old Tg2576 mice, received a single iv injection of 30 mg of the TOMA antibody. Control group received 30 mg of non-specific IgG. Cognitive function was assessed by novel object recognition test, 15 days after injection. In addition, western blot, ELISA and Immunostaining were performed to evaluate the response to treatment. Results: Our results indicate that single iv-injection of the TOMA antibody, reduce endogenous tau oligomers and improve cognition in the Tg2576 mouse. Interestingly, removal of tau oligomers by immunotherapy decreases beta-amyloid-56* and increases deposition of plaques in immunized mice. Conclusions: Our results support the findings that tau oligomers mediate beta-amyloid toxicity in vivo. Moreover, removal of tau oligomers by immunotherapy may induce beta-amyloid aggregates to assembly into inert and perhaps protective plaques. Thus, targeting tau oligomers by immunotherapymay represent a novel strategy for the treatment of AD and other neurodegenerative tauopathies.