Abstract
We present here the first description of tau in human dental pulp stem cells (DPSCs) evidenced by RT-PCR data on expression of the gene MAPT and by immunocytochemical detection of epitopes by 12 anti-tau antibodies. The tau specificity of eight of these antibodies was confirmed by their affinity to neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) postmortem brain samples. We therefore used DPSCs and AD brain samples as a test system for determining the probability of the involvement of tau epitopes in the mechanisms converting tau into NFT in AD. Three antibodies to non-phosphorylated and seven antibodies to phosphorylated epitopes bound tau in both DPSCs and AD NFTs, thus suggesting that their function was not influenced by inducers of formation of NFTs in the AD brain. In contrast, AT100, which recognizes a hyperphosphorylated epitope, did not detect it in the cytoplasm of DPSCs but detected it in AD brain NFTs, demonstrating its AD diagnostic potential. This indicated that the phosphorylation/conformational events required for the creation of this epitope do not occur in normal cytoplasm and are a part of the mechanism (s) leading to NFT in AD brain. TG3 bound tau in the cytoplasm and in mitotic chromosomes but did not find it in nuclei. Collectively, these observations characterize DPSCs as a novel tau-harboring neuronal lineage long-term propagable in vitro cellular system for the normal conformational state of tau sites, detectable by antibodies, with their state in AD NFTs revealing those involved in the pathological processes converting tau into NFTs in the course of AD. With this information, one can model the interaction of tau with inducers and inhibitors of hyperphosphorylation toward NFT-like aggregates to search for drug candidates. Additionally, the clonogenicity of DPSCs provides the option for generation of cell lineages with CRISPR-mutagenized genes of familial AD modeling.
Highlights
Alzheimer’s disease (AD), characterized by neuronal cell death, is the most widespread and harmful neurodegenerative disease in the world, and it accounts for more than a half of all cases of dementia [1, 2]
We describe for the first time the presence of an endogenous tau protein in human dental pulp stem cells (DPSCs) evidenced by the detection of its nonphosphorylated and phosphorylated epitopes by a panel of tauspecific antibodies, some of which are used for characterization of tau modifications in the AD
Non-phosphorylated and phosphorylated tau immunoreactivity in neurofibrillary tangles (NFTs) from the AD brain was tested. It was done with two purposes: (a) to serve as a positive control for the tau immunochemical assay in DPSCs and (b) to obtain information about the antigenically functional state of the tau epitopes in NFTs
Summary
Alzheimer’s disease (AD), characterized by neuronal cell death, is the most widespread and harmful neurodegenerative disease in the world, and it accounts for more than a half of all cases of dementia [1, 2]. The alternative splicing of MAPT generates six isoforms of tau in the central nervous system (CNS) [(11–17), reviewed in [18]]. Tau function and pathogenesis are restricted to the cytoplasm; the meaning of its presence in nuclei [26,27,28] remains generally understudied. Tau abnormalities are commonly observed in many neurodegenerative diseases including AD, Parkinson’s disease, and Pick’s disease. Phosphorylated tau monomers lose their affinity for microtubules, self-assembling to form insoluble aggregations or paired helical filaments (PHFs), which are the precursors of neurofibrillary tangles (NFTs) [32, 33] considered a key marker of AD [34]. Phosphorylation of tau results in microtubule instability, ineffective transport of molecules and organelles, and incompatibility with neuronal function
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