Tau‐targeting passive immunization modulates aspects of pathology in tau transgenic mice

Abstract

Immunization is increasingly recognized as a suitable therapeutic avenue for the treatment of neurological diseases such as Alzheimer's disease and other tauopathies. Tau is a key molecular player in these conditions and therefore represents an attractive target for passive immunization approaches. We performed such an approach in two independent tau transgenic mouse models of tauopathy, K369I tau transgenic K3 and P301L tau transgenic pR5 mice. The antibodies we used were either specific for full-length tau or tau phosphorylated at serine 404 (pS404), a residue that forms part of the paired helical filament (PHF)-1 phosphoepitope that characterizes tau neurofibrillary tangles in tauopathies. Although both pS404 antibodies had a similar affinity, they differed in isotype, and only passive immunization with the IgG2a/j pS404-specific antibody resulted in a lower tangle burden and reduced phosphorylation of tau at the PHF1 epitope in K3 mice. In pR5 mice, the same antibody led to a reduced phosphorylation of the pS422 and PHF1 epitopes of tau. In addition, histological sections of the hippocampal dentate gyrus of the immunized pR5 mice displayed reduced pS422 staining intensities. These results show that passive immunization targeting tau can modulate aspects of tau pathology in tau transgenic mouse models, in an antibody isotype-specific manner.

Tau immunotherapy for Alzheimer's disease

“…These investigators evaluated three tau antibodies in the K369I (K3) transgenic tau mouse and in a P301L mouse model [71]. Antibodies with varying properties were selected for in vivo evaluation.…”

Effects of antibodies to phosphorylated and non-phosphorylated tau on in vitro tau phosphorylation at Serine-199: Preliminary report

“…Wood and Zinsmeister (1989) found that the anti-tau monoclonal antibodies Alz-50 and Tau-1 each blocked the binding of the other antibody to neurofibrillary tangles (NFTs) and neuritic plaques. Ittner et al (2015) similarly reported that administration of anti-pTau S404 antibody to transgenic tauopathy mice reduced the staining intensity of pS422 in hippocampal dental gyrus neurons. However, this result could have been due either to decreased phosphorylation of tau at S422 or to increased clearance of the pS422-reactive neurons.…”

“…In transgenic "tauopathy" mice which express human tau mutations, immunization with phosphorylated tau fragments (Asuni et al, 2007;Boimel et al, 2010) and administration of monoclonal antibodies specific for phosphorylated tau (Chai et al, 2011;Ittner et al, 2015) were found to reduce the development of tau pathology. Treatment with antibodies to non-phosphorylated tau also decreased brain levels of phosphorylated tau in tauopathy mice (Dai et al, 2015).…”

Humanization of a phosphothreonine peptide-specific chicken antibody by combinatorial library optimization of the phosphoepitope-binding motif

“…(For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) protein [26] and also serve as a valuable template for generating a pThr-peptide-focused human antibody library to bypass animal immunization [6].…”