Immunotherapy Targeting Pathological Tau Conformers in a Tangle Mouse Model Reduces Brain Pathology with Associated Functional Improvements

Abstract

Immunotherapies for various neurodegenerative diseases have recently emerged as a promising approach for clearing pathological protein conformers in these disorders. This type of treatment has not been assessed in models that develop neuronal tau aggregates as observed in frontotemporal dementia and Alzheimer's disease. Here, we present that active immunization with a phosphorylated tau epitope, in P301L tangle model mice, reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. Females had more tau pathology than males but were also more receptive to the immunotherapy. The tau antibodies generated in these animals recognized pathological tau on brain sections. Performance on behavioral assays that require extensive motor coordination correlated with tau pathology in corresponding brain areas, and antibody levels against the immunogen correlated inversely with tau pathology. Interestingly, age-dependent autoantibodies that recognized recombinant tau protein but not the immunogen were detected in the P301L mice. To confirm that anti-tau antibodies could enter the brain and bind to pathological tau, FITC-tagged antibodies purified from a P301L mouse, with a high antibody titer against the immunogen, were injected into the carotid artery of P301L mice. These antibodies were subsequently detected within the brain and colocalized with PHF1 and MC1 antibodies that recognize pathological tau. Currently, no treatment is available for clearing tau aggregates. Our present findings may lead to a novel therapy targeting one of the major hallmarks of Alzheimer's disease and frontotemporal dementia.

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…205 In the case of tau, P301L transgenic mice were immunized with a phospho-tau peptide (containing the phosphorylated PHF-1 epitope). 196 These mice responded with antibody synthesis, less of histochemically detectable tau aggregates, and slower progression of behavior deficits, compared with untreated mice. The feasibility of tauimmunotherapy must be considered critically, however, given that vaccination of C57BL/6 mice with recombinant human tau protein resulted in the onset of neurofibrillary tangle pathology, axon damage, demyelination, and gliosis.…”

“…[192][193][194][195] Similar vaccination approaches have been tested for a tau-directed immunotherapy in mice, even though tau aggregates are intracellular (in contrast to amyloid plaques). 196,197 Neuronal pinocytic uptake of antibodies has been reported, partially mediated by the neuronal Fc␥ or Thy1.1 receptors. 198 -204 This increases the probability of targeting intracellular tau by an antibody-mediated approach.…”

“Clicked” Sugar–Curcumin Conjugate: Modulator of Amyloid-β and Tau Peptide Aggregation at Ultralow Concentrations

“…Therapeutic approaches for reduction of phosphorylated tau include pharmacologic manipulation of cellular protein refolding/ degradation pathways 8 and immunotherapy. 9 It is evident from the above discussion that there are many pathways that contribute to AD. An ideal AD drug candidate should therefore be broad spectrum with activity against all the pathways that contribute to AD.…”

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

“…Numerous mouse tauopathy models have also been used to assess the efficacy of active immunization [104][105][106][107] and passive immunization [54,108] against tau protein. These studies are encouraging for the development of effective immune-based strategies.…”