COMPARISON OF PLASMA Aβ ASSAYS AS PHARMACODYNAMIC READ-OUT FOR BACE1 INHIBITOR TREATMENT IN CANINES

Abstract

Background:With the urgent need to find an optimal therapeutic approach in Alzheimer’s disease (AD), immunization studies have been continuously performed with limited success till date. Intravenous immunoglobulins (IVIgs), a mix of purified human plasma product collected from a large pool of healthy donors, have been used as an alternative agent for immunotherapy. Anti-amyloid properties of IVIgs against Ab have been tested in pilot studies showing cognitive improvements in mild-to-moderately affected AD patients. According to a recent study, IVIgs also contain antibodies to recombinant human tau. In-depth analyses of anti-amyloid antibodies present in IVIg preparations are of great importance in order to optimize their role as a disease modifying therapeutic agent. Herein, we studied the presence of tau oligomer-specific antibodies in IVIg preparations, which with further characterization may provide neuroprotection in AD and other tauopathies. Methods: We used three different commercially available IVIg preparations: Gammagard (Baxter), Gamunex (Talecris) and Privigen (CSL Behring), a well-characterized anti-tau oligomer specific antibody (T22), as well as commercial generic tau antibodies for elaborate biochemical analyses of recombinant full-length tau aggregates and oligomers. Additionally, IVIg Gamunex was used to immunoprecipitate recombinant tau oligomers. Results: Western blot analyses with IVIg products consistently revealed strong immunoreactivity against recombinant tau oligomers at different molecular weights, from 75 kDa to 250 kDa and above, which was confirmed with generic tau antibodies. Direct ELISA analysis of stable tau oligomers preparations with IVIgs also demonstrated the presence of antibodies against tau oligomers in these preparations. Additionally, we immunoprecipitated tau oligomers from a stable oligomeric preparation using Gamunex which was also reconfirmed by immunoblotting with T22 and generic tau antibodies. Conclusions: To our knowledge, this is the first study which identifies the presence of endogenous antibodies from IVIgs against multiple conformers of tau aggregates and neurotoxic tau oligomers. Furtherextensive study is necessary for complete characterization of these naturally occurring tau antibodies, as well as these immunoglobulin preparations, which together would provide a better understanding of their potential beneficial mechanisms for AD and other neurodegenerative diseases.