Abstract
Tau, the main component of the neurofibrillary tangles (NFTs), is an attractive target for immunotherapy in Alzheimer’s disease (AD) and other tauopathies. MC1/Alz50 are currently the only antibodies targeting a disease-specific conformational modification of tau. Passive immunization experiments using intra-peritoneal injections have previously shown that MC1 is effective at reducing tau pathology in the forebrain of tau transgenic JNPL3 mice. In order to reach a long-term and sustained brain delivery, and avoid multiple injection protocols, we tested the efficacy of the single-chain variable fragment of MC1 (scFv-MC1) to reduce tau pathology in the same animal model, with focus on brain regional differences. ScFv-MC1 was cloned into an AAV delivery system and was directly injected into the hippocampus of adult JNPL3 mice. Specific promoters were employed to selectively target neurons or astrocytes for scFv-MC1 expression. ScFv-MC1 was able to decrease soluble, oligomeric and insoluble tau species, in our model. The effect was evident in the cortex, hippocampus and hindbrain. The astrocytic machinery appeared more efficient than the neuronal, with significant reduction of pathology in areas distant from the site of injection. To our knowledge, this is the first evidence that an anti-tau conformational scFv antibody, delivered directly into the mouse adult brain, is able to reduce pathological tau, providing further insight into the nature of immunotherapy strategies.
Highlights
In Alzheimer’s disease (AD), neurofibrillary pathology positively correlates with cognitive decline, emphasizing the direct link between pathological tau accumulation and neurodegeneration [8, 9, 30, 39, 50]
In conventional passive immunotherapy studies performed in mice, we and others [14, 17] have previously shown that targeting the MC1 epitope can efficiently reduce neurofibrillary pathology in forebrain, highlighting the importance of tau epitope specificity: the ability to discriminate between normal tau and pathological tau species confers MC1 a remarkable advantage as immunotherapeutic tool compared to pan-tau and phospho-tau antibodies, which on the contrary might interfere with the normal function of tau
ScFv-MC1 is efficiently secreted in vitro, and its antigenbinding specificity is comparable to the MC1 parent antibody ScFv-MC1 was expressed in the HEK293T cell line in order to assess for efficient secretion in medium
Summary
In Alzheimer’s disease (AD), neurofibrillary pathology positively correlates with cognitive decline, emphasizing the direct link between pathological tau accumulation and neurodegeneration [8, 9, 30, 39, 50]. MC1 and Alz are the only tau antibodies targeting the AD-specific epitope formed by two discontinuous portions of tau, 7EFE9 and 313VDLSKVTSKC322 [21, 28, 29]. This aberrant conformation of tau was shown to be present in a soluble form of the protein and in paired helical filaments (PHF) assemblies [47]. Of note, humanized MC1 (LY3303560) has recently entered a Phase II study to treat early symptomatic Alzheimer’s disease [ClinicalTrials.gov, accession number NCT03518073]
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