Passive Immunization with Phospho-Tau Antibodies Reduces Tau Pathology and Functional Deficits in Two Distinct Mouse Tauopathy Models

Abstract

In Alzheimer’s disease (AD), an extensive accumulation of extracellular amyloid plaques and intraneuronal tau tangles, along with neuronal loss, is evident in distinct brain regions. Staging of tau pathology by postmortem analysis of AD subjects suggests a sequence of initiation and subsequent spread of neurofibrillary tau tangles along defined brain anatomical pathways. Further, the severity of cognitive deficits correlates with the degree and extent of tau pathology. In this study, we demonstrate that phospho-tau (p-tau) antibodies, PHF6 and PHF13, can prevent the induction of tau pathology in primary neuron cultures. The impact of passive immunotherapy on the formation and spread of tau pathology, as well as functional deficits, was subsequently evaluated with these antibodies in two distinct transgenic mouse tauopathy models. The rTg4510 transgenic mouse is characterized by inducible over-expression of P301L mutant tau, and exhibits robust age-dependent brain tau pathology. Systemic treatment with PHF6 and PHF13 from 3 to 6 months of age led to a significant decline in brain and CSF p-tau levels. In a second model, injection of preformed tau fibrils (PFFs) comprised of recombinant tau protein encompassing the microtubule-repeat domains into the cortex and hippocampus of young P301S mutant tau over-expressing mice (PS19) led to robust tau pathology on the ipsilateral side with evidence of spread to distant sites, including the contralateral hippocampus and bilateral entorhinal cortex 4 weeks post-injection. Systemic treatment with PHF13 led to a significant decline in the spread of tau pathology in this model. The reduction in tau species after p-tau antibody treatment was associated with an improvement in novel-object recognition memory test in both models. These studies provide evidence supporting the use of tau immunotherapy as a potential treatment option for AD and other tauopathies.

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

“…In transgenic mouse models, passive transfer of tau-specific antibodies can reduce tau pathology (20,(33)(34)(35). Similar approaches in humans are being widely studied as potential treatments for neurodegeneration (36).…”

Tau: From research to clinical development

“…For example, tau anti-sense oligonucleotides and siRNAs may work through a variety of mechanisms, including a reduction in the levels of phosphorylated tau, moderation of RNA splicing, tau silencing, and blockade of tau seeding [57,58]. Immunotherapy also offers several possible therapeutic pathways, including blocking neuronal uptake of tau aggregates and promoting clearance of aggregates by microglia [59][60][61][62].…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…2), or by blocking neuronal uptake of the protein [143]. Passive immunization with antiphospho-tau antibodies reduce tau pathology and functional deficits [137,[144][145][146], and antibodies targeting tau oligomers have also shown promise in transgenic models [136,147], including a concomitant upstream reduction in Aβ pathology [148]. In this sense, there are 3 anti-tau antibodies currently being studied in phase I trials (Table 1).…”