Abstract
Tauopathies are neurodegenerative diseases characterized by the intraneuronal accumulation of aggregated tau. The staging of this neurodegenerative process is well established for Alzheimer's disease as well as for other tauopathies. The stereotypical pattern of tau pathology in these diseases is consistent with the hypothesis that the tau protein can spread in a 'prion-like' manner. It proposes that extracellular pathological tau species can transmit pathology from cell to cell. Accordingly, by targeting these spreading species with therapeutic antibodies one should be able to slow or halt the progression of tau pathology. To be effective, antibodies should neutralize the pathological species present in Alzheimer's disease brains and block their cell-to-cell spread. To evaluate both aspects, tau antibody D, which recognizes an epitope in the central region of tau, and was selected for its outstanding ability to block tau seeding in cell based assays, was used in this study. Here, we addressed two fundamental questions: (i) can this anti-tau antibody neutralize the pathological species present in Alzheimer's disease brains; and (ii) can it block the cell-to-cell spread of tau seeds in vivo? First, antibody D effectively prevented the induction of tau pathology in the brains of transgenic mice that had been injected with human Alzheimer's disease brain extracts, showing that it could effectively neutralize the pathological species present in these extracts. Second, by using K18 P301L tau fibrils to induce pathology, we further demonstrated that antibody D was also capable of blocking the progression of tau pathology to distal brain regions. In contrast, an amino-terminal tau antibody, which was less effective at blocking tau seeding in vitro showed less efficacy in reducing Alzheimer's disease patient tau driven pathology in the transgenic mouse model. We did not address whether the same is true for a spectrum of other amino-terminal antibodies that were tested in vitro. These data highlight important differences between tau antibodies and, when taken together with other recently published data, suggest that epitope may be important for function.
Highlights
The tau protein is considered to be an intracellular neuronal protein involved in microtubule polymerization and stabilization (Weingarten et al, 1975)
We injected K18-P301L in hTauP301L transgenic mice (Peeraer et al, 2015); tau fibrils that are not recognized by tau antibody D. We demonstrated in this model that antibody D is capable of blocking the progression of tau pathology to distal brain regions, as the therapeutic antibody cannot bind to the injected material, it unambiguously demonstrates an effect on spread, even though the seed is artificial
The idea that tau pathology may spread in a ‘prion-like’ manner was first proposed some time ago (Alonso et al, 1996; Su et al, 1997)
Summary
The tau protein is considered to be an intracellular neuronal protein involved in microtubule polymerization and stabilization (Weingarten et al, 1975). The hyperphosphorylation and deposition of tau proteins in insoluble aggregates inside neurons is a hallmark of around 20 pathologies termed tauopathies; these include the well-known Alzheimer’s disease (Spillantini et al, 1998; Buee et al, 2000). These pathologies differ by both the content in tau isoforms [three (3R)- or four (4R)-microtubule-binding domains] and the regional distribution of tau aggregates. This propagation could occur in a ‘prion-like’ manner involving transfer of abnormal tau seeds from a donor cell to a recipient cell in which the recruitment of normal tau generates new tau seeds (Clavaguera et al, 2009; de Calignon et al, 2012; for a review see Mudher et al, 2017)
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