期刊
BRAIN
卷 142, 期 -, 页码 1736-1750出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awz100
关键词
immunotherapy; Alzheimer's disease; seeding; propagation
资金
- UCB Biopharma SPRL
- program Investissement d'avenir LabEx (laboratory excellence) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) [ANR-14-CE13-0031, TONIC ANR-18-CE44-0016]
- LiCEND (Lille Centre of Excellence in Neurodegenerative Disorders)
- CNRS
- Inserm
- Metropole Europeenne de Lille
- DN2M
- Agence Nationale de la Recherche (ANR) [ANR-14-CE13-0031] Funding Source: Agence Nationale de la Recherche (ANR)
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.
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