Targeting Phospho-Ser422 by Active Tau Immunotherapy in the THYTau22 Mouse Model: A Suitable Therapeutic Approach

Abstract

Recent data indicate that Tau immunotherapy may be relevant for interfering with neurofibrillary degeneration in Alzheimer disease and related disorders referred to as Tauopathies. The key question for immunotherapy is the choice of the epitope to target. Abnormal phosphorylation is a well-described post-translational modification of Tau proteins and may be a good target. In the present study, we investigated the effects of active immunization against the pathological epitope phospho-Ser422 in the THY-Tau22 transgenic mouse model. Starting from 3-6 months of age, THY-Tau22 mice develop hippocampal neurofibrillary tangle-like inclusions and exhibit phosphorylation of Tau on several AD-relevant Tau epitopes. Three month-old THY-Tau22 mice were immunized with a peptide including the phosphoserine 422 residue while control mice received the adjuvant alone. A specific antibody response against the phospho-Ser422 epitope was observed. We noticed a decrease in insoluble Tau species (AT100- and pS422 immunoreactive) by both biochemical and immunohistochemical means correlated with a significant cognitive improvement using the Y-maze. This Tau immunotherapy may facilitate Tau clearance from the brain toward the periphery since, following immunization, an increase in Tau concentrations was observed in blood. Overall, the present work is, to our knowledge, the first one to demonstrate that active immunotherapy targeting a real pathological epitope such as phospho-Ser422 epitope is efficient. This immunotherapy allows for Tau clearance and improves cognitive deficits promoted by Tau pathology in a well-defined Tau transgenic model.

Epitope analysis following active immunization with tau proteins reveals immunogens implicated in tau pathogenesis

“…The beneficial effects of tau immunotherapy have been previously demonstrated by several research laboratories [8,10,11,19,21,28]. To date, there have been no investigations of immunogenicity of various forms of tau protein or subsequent humoral and cellular immune responses following vaccination.…”

“…However, when tau is phosphorylated at S422, its caspase cleavage is blocked and this phospho-tau species is also found in tangle pathology. In fact, a previous study showed that active immunization targeting pS422 in tau transgenic mice led to an immune response and reduction of tau pathology followed by significant cognitive improvement [21]. These findings suggest that multiple factors can contribute to tau pathology, and the interface between the biology and immunological response to these distinct tau species could be essential to designing improved treatments targeting tau.…”

“…Passive immunization strategies have shown great promise in pre-clinical models. Studies have shown that FITC-labeled antibodies can not only cross the blood-brain barrier [21] but also enter neurons and bind intracellular tau both in vivo and ex vivo [10,50]. In fact, these internalized antibodies co-localize with pathological tau markers inside the neurons containing tau pathology [20], and can prompt the clearance of intracellular tau aggregates through the endosomal/lysosomal system [51,52].…”

“…Indeed, active immunization of mice with tau peptides produced tau antibodies that could cross the blood-brain barrier, (BBB) reduce pathological tau [1,20], and rescue functional impairments in tau transgenic mice [9,10,21]. So far, however, these peptides have all been generated based on pathological relevance or predicted immunogenicity using algorithms; there has not been an epitope map produced to identify the strongest immunogens in the tau sequence.…”

Editorial (Thematic Issue: Overview of Immunotherapy in Alzheimer’s Disease (AD) and Mechanisms of IVIG Neuroprotection in Preclinical Models of AD)

“…Notably, an active immunotherapy targeting the tau pathological epitope phospho-Ser422 was found to be efficient, resulting in tau clearance and improved cognitive deficits promoted by tau pathology in a well-defined tau transgenic model [15]. Like Aβ oligomers, the putative role of tau oligomers in AD pathophysiology has prompted an investigation into tau oligomers as potential immunotherapeutic targets for AD and tauopathies [16].…”